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DTT 2023; 2(2): 133-144

Published online September 30, 2023 https://doi.org/10.58502/DTT.23.0012

Copyright © The Pharmaceutical Society of Korea.

Roles of Coffee and Its Components in Liver Diseases

Eun Seon Pak , Seojeong Park , Hyeri Yoon, Seojeong Kim , Youngjoo Kwon

College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Korea

Correspondence to:Youngjoo Kwon, ykwon@ewha.ac.kr

Received: April 4, 2023; Revised: May 30, 2023; Accepted: June 7, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ((http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Coffee is a widely consumed beverage with multifaceted health benefits. While several studies have explored its effects on various diseases, limited reports have investigated its association with liver disease. Therefore, this review aimed to explore the effects of coffee consumption and its major coffee components on liver disease. Meta-analysis results have suggested that coffee consumption may reduce the risk of non-alcoholic fatty liver disease, hepatic fibrosis, and hepatocellular carcinoma, but the molecular mechanisms underlying these beneficial actions of coffee consumption remain elusive. Studying the individual components of coffee could help us better understand the mechanisms behind its liver protective effects. To clarify a more precise mechanism of coffee-related liver protective effects, the experimentally determined effects of each coffee component on liver diseases are also reviewed.

Keywordsnon-alcoholic fatty liver disease (NAFLD), hepatic fibrosis, hepatocellular carcinoma, coffee, kahweol, cafestol

Coffee, one of the most widely consumed beverages worldwide, has been extensively studied for its multifaceted effects on human health. Several meta-analyses suggest a non-linear association between coffee consumption and health outcomes. Compared to not drinking coffee, moderate coffee consumption (1-2 cups, 2-3 cups, or 3-5 cups per day, with slight variations between studies) is beneficial in reducing the risk of all-cause mortality, heart failure, and cardiovascular diseases (Ding et al. 2014; Poole et al. 2017; Stevens et al. 2021; Chieng et al. 2022). In addition, cohort studies have shown that moderate coffee consumption, alone or combined with tea, is linked to a lower risk of stroke, dementia, and post-stroke dementia (Chan et al. 2021; Zhang et al. 2021). Another prospective cohort study found that moderate coffee consumption reduced the hazard ratio for coronary heart disease, but showed no significant association with cancer mortality or stroke (Shahinfar et al. 2021). Heavy coffee drinkers appear to have a lower risk of certain cancers, including oral and liver cancers, as well as diseases affecting the nervous system, metabolism, and liver, compared to light coffee drinkers (Poole et al. 2017).

In contrast to the above studies, excessive coffee consumption (> 6 cups per day) has been associated with a modest increase in the risk of cardiovascular disease (Zhou and Hyppönen 2019). In addition, coffee consumption is not recommended for pregnant women or women at high risk of fractures (Poole et al. 2017). These conflicting findings highlight the need for further research to establish a definitive association between coffee consumption and specific diseases, taking into account variables such as the participants’ medical history, the type of coffee consumed, drinking patterns with and without additives such as sugar or milk, and other relevant parameters specific to each disease. Although numerous cohort studies or review papers have suggested that coffee consumption is beneficial for cardiovascular diseases (Ding et al. 2014; Poole et al. 2017; Zhou and Hyppönen 2019; Shahinfar et al. 2021; Stevens et al. 2021; Chieng et al. 2022), few reports have explored the relationship between coffee consumption and liver diseases.

Here, this paper specifically aims to review the effects of coffee consumption and major components of coffee, such as caffeine, cafestol, kahweol, and chlorogenic acids, on liver diseases.

After conducting a literature search on PubMed using the search term “coffee, cohort study, and liver disease” for the past 10 years up to February 2023, we were able to identify 70 relevant papers. Some papers investigated the relationship between liver diseases and dietary patterns, including the consumption of alcohol, coffee, and tea, types of alcoholic beverages, smoking, sleep duration, and more (Kaenkumchorn et al. 2021; Mikolasevic et al. 2021; Doustmohammadian et al. 2022). We focused on papers reporting an association between coffee consumption and liver disease to extract more precise information about the effects of coffee on liver diseases.

It has been observed in patients with chronic hepatitis C that consuming 3-5 cups of coffee per day was associated with a reduction in oxidative damage, an increase in telomere length, and a decrease in apoptotic cell death. Additionally, coffee consumption has been shown to reduce collagen synthesis, which is a factor that mediates the protection exerted by coffee against liver disease progression (Cardin et al. 2013). A Meta-analysis of case-control studies and cohort studies suggested a potential inverse association between coffee consumption and the incidence and progression of liver cancer and cirrhosis (Bravi et al. 2013; Sang et al. 2013; Petrick et al. 2015; Setiawan et al. 2015; Kennedy et al. 2016; Wang et al. 2016; Alicandro et al. 2017; Bravi et al. 2017; Godos et al. 2017; Kennedy et al. 2017; Tamura et al. 2018; Tran et al. 2019; Wiltberger et al. 2019; Bhurwal et al. 2020; Di Maso et al. 2021; Kennedy et al. 2021; Kim et al. 2021). Recent cohort studies found that coffee consumption may help reduce the risk of non-alcoholic fatty liver disease (NAFLD), hepatic fibrosis, and hepatocellular carcinoma (HCC) through inhibition of inflammation and oxidative stress (Tan et al. 2021; Barré et al. 2022; Zheng et al. 2022). In addition, coffee consumption alters the composition of the duodenal microbiome in cirrhosis, suggesting that this may contribute to health benefits (Bajaj et al. 2018; Hussain et al. 2020). Interestingly, another meta-analysis showed no association between coffee consumption and NAFLD incidence, but a significant association with reduced probability of liver fibrosis (Ebadi et al. 2021). On the other hand, coffee consumption was not associated with liver fibrosis and its progression to HCC in patients with chronic hepatitis B infection (Chen et al. 2019; Brahmania et al. 2020) and not associated with any lower hepatic steatosis in both non-alcoholic and alcoholic liver diseases (Veronese et al. 2018). Due to these conflicting cohort results, it is necessary to analyze cohort results with better managing the number of participants and diverse variables related to liver diseases, or to perform further studies on the mechanism of action.

The molecular mechanisms underlying the beneficial association between coffee consumption and the reduced risk of liver diseases, including fatty liver, HCC, and liver fibrosis, remain elusive. A recent epigenome-wide association study provided that high coffee consumption was associated with lower levels of DNA methylation at cytosine-phosphate guanine (CpG) sites annotated to the AHRR, F2RL3, FLJ43663, HDAC4, GFI1, and PHGDH genes. Among them, further experiments with PHGDH knock-down in liver cells showed that the association between coffee consumption and fatty liver disease could be mediated by PHGDH expression by altering DNA methylation levels at cg14476101 (Karabegović et al. 2021). PHGDH encodes phosphoglycerate dehydrogenase that catalyzes the conversion of 3-phosphoglycerate to 3-phosphohydroxypyruvate, a step in the phosphorylation pathway of serine biosynthesis (Wahl et al. 2017). As a rich source of phenolic phytochemicals, the health-promoting effects of coffee, such as lowering the risk of HCC and cirrhosis, might be attributed to its ability to upregulate proteins involved in cell protection, particularly antioxidant, detoxifying, and repair enzymes, by activating the nuclear factor erythroid 2-related factor-2 (Nrf2) system (Kolb et al. 2020). Coffee consumption has been also shown to have anti-inflammatory effects by downregulating markers such as interleukin-6 (IL-6) (Aleksandrova et al. 2015), chemokine (C-X3-C motif) ligand 1 (CX3CL1) (Jones et al. 2010), chemokine (C-C motif) ligands 4 (CCL4), interferon γ (IFNγ), and fibroblast growth factor 2 (FGF-2) (Loftfield et al. 2015). Various cohort studies have suggested the beneficial effects of coffee consumption on liver diseases, through either altering post-translational modification or inhibiting inflammation, oxidative stress, and fibrosis. Further detailed mechanistic studies of the individual components of coffee are needed to better understand the specific mechanisms underlying the benefits of coffee consumption for liver diseases.

Coffee contains various bioactive compounds such as caffeine, diterpenes, chlorogenic acids, and melanoidins, which may have different effects on liver health (Hu et al. 2019). Unfortunately, cohort studies of each coffee component other than caffeine have not yet been reported. Therefore, the individual effects of coffee components on liver diseases that have been experimentally determined are summarized in the following sections.

Caffeine

Caffeine (Fig. 1A), one of the primary components of coffee, contains a purine ring, which chemically resembles adenosine and acts as a non-selective receptor antagonist of adenosine (Eltzschig et al. 2012). Caffeine metabolism occurs mainly by the cytochrome P-450 1A2 (CYP1A2) enzyme present in the liver (Amchin et al. 1999; Kot and Daniel 2008). Thus, caffeine clearance is considered a measure of CYP1A2 activity. Previous studies found that decreased CYP1A2 activity leading to a reduction in caffeine clearance was associated with NAFLD progression (Perera et al. 2013). Furthermore, liver diseases including cirrhosis, hepatitis B, and hepatitis C cause the impaired elimination of caffeine (Desmond et al. 1980; Scott et al. 1988). These studies suggested reduction of caffeine clearance was associated with liver diseases, yet more studies are needed.

Figure 1.Structures of coffee components. (A) Caffeine. (B) Kahweol. (C) Cafestol. (D-F) Chlorogenic acids, formed by the esterification of quinic acid with caffeic acid (D), ferulic acid (E), and p-coumaric acid (F). (G) Basic structure of melanoidins.

Lipid accumulation in the liver is a pathophysiological hallmark of NAFLD (Pei et al. 2020). Interestingly, caffeine has been shown to increase fat oxidation (Acheson et al. 1980) and energy expenditure (Astrup et al. 1990). These effects suggest a potential role of caffeine to enhance lipid metabolism. Inhibition of lipid accumulation of caffeine was associated with the regulation of low-density lipoprotein receptor (LDLR) expression (Lebeau et al. 2022). A recent study showed that caffeine reduced levels of circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) in healthy volunteers (Lebeau et al. 2022). In addition, caffeine-induced increase in the hepatic endoplasmic reticulum (ER) calcium level inhibited the transcriptional activation of sterol regulatory element binding protein 2 (SREBP2), which is responsible for regulating PCSK9 expression, leading to increased LDLR expression and promotion of low-density lipoprotein cholesterol (LDLc) clearance (Lebeau et al. 2022). This effect of caffeine may be one of the mechanisms of action supporting the beneficial effect of coffee consumption on lipid metabolism disorders resulting in cardiovascular and chronic liver disease.

Liver fibrosis is a pathophysiological process characterized by abnormal tissue proliferation, which is caused by non-alcoholic steatohepatitis (NASH) and NAFLD (Aydın and Akçalı 2018). A systematic review and meta-analysis found that regular caffeine intake from coffee was significantly associated with reduced liver fibrosis in NAFLD (Shen et al. 2016). Caffeine consumption, approximately 2 coffee cups per day, alleviated liver fibrosis (Modi et al. 2010). One well-known mechanism by which caffeine exerts anti-fibrotic effects in the liver is through its function as an adenosine receptor antagonist (Chan et al. 2006). Indeed, caffeine blocked adenosine A2A receptor-mediated fibrosis (Chan et al. 2006). Caffeine inhibited liver fibrosis-induced adenosine A2A receptor activation through upregulation of peroxisome proliferator-activated receptor γ (PPARγ) and reduction of SMAD2/3 (Gressner et al. 2008). Caffeine inhibited matrix metalloproteinases (MMPs) secretion and reduced α-smooth muscle actin (α-SMA) in liver fibrosis (Amer et al. 2017). With increasing evidence of the beneficial role of caffeine in liver disease, caffeine may be a potential therapeutic agent for treating liver diseases (Fig. 2).

Figure 2.Effect of caffeine on liver diseases. Caffeine has anti-cholesterol, anti-fibrotic, and anti-lipid accumulation effects. The marker ↓ indicates inhibition, and indicates receptor blocking. CYP1A2, cytochrome P-450 1A2; LDL, low-density lipoprotein; LDLc, low-density lipoprotein cholesterol; PCSK9, proprotein convertase subtilisin/kexin type 9; PPAR γ, peroxisome proliferator-activated receptor γ; SREBP2, sterol regulatory element binding protein 2; α-SMA, α-smooth muscle actin.

Kahweol and cafestol

Kahweol (Fig. 1B) and cafestol (Fig. 1C) are diterpenoid molecules and are structurally similar to each other. Kahweol and cafestol are the major antioxidative components of coffee and have been considered as components responsible for the proposed biological and pharmacological effects of coffee (Ludwig et al. 2014; Ren et al. 2019).

Kahweol has been shown to possess antioxidant and anti-inflammatory properties, making it effective in mitigating acetaminophen-induced liver damage in mice. This was achieved by restoring glutathione content, inhibiting endoplasmic reticulum (ER) stress-induced cell death in hepatocytes, stimulating the Nrf2-dependent cellular defense system, and reducing NK-κB-mediated inflammation (Kim et al. 2022). The ability of kahweol to increase Nrf2 expression was attributed to its reduction of Keap1 protein expression, which occurred independently of p62-dependent autophagy degradation (Seo et al. 2020). Furthermore, kahweol and cafestol exhibited potent hepatoprotective effects against CCl4-induced oxidative stress in mice. These effects were attributed to their ability to inhibit the activity of CYP2E1, thus blocking the bioactivation of CCl4. As a result, the formation of trichloromethyl radicals is decreased, and the antioxidant and free radical-scavenging activities of kahweol and cafestol were able to prevent lipid peroxidation and subsequent hepatocellular injury (Lee et al. 2007). Kahweol reduced the production of several pro-inflammatory cytokines, including IL-1, IL-6, and TNF-α, which are known to be involved in hepatitis, liver fibrosis, and cirrhosis. The inhibitory effect of kahweol on liver inflammation was due to its ability to downregulate the expression of two important transcription factors, phospho-NF-κB and phospho-STAT3 in HCC cells (Seo et al. 2018). These transcription factors are known to play a key role in the activation of inflammatory pathways and are often dysregulated in liver diseases such as hepatitis and liver cancer (Schmidt-Arras and Rose-John 2016; Sultan et al. 2017). Cafestol treatment before inducing hepatic ischemia-reperfusion injury reduced the levels of pro-inflammatory cytokines, markers of apoptosis, and autophagy in the mouse liver tissue. The liver protective effects of cafestol were associated with the suppression of the ERK/PPARγ pathway, which plays a key role in regulating both inflammation and oxidative stress (Han et al. 2016; Ji et al. 2020).

In a study using a thioacetamide (TAA)-induced hepatic fibrosis mouse model, kahweol treatment was found to significantly attenuate liver fibrosis by inhibiting the TAA-induced activation of several signaling pathways, including p-STAT3, pERK, and pJNK (Seo et al. 2017). These signaling pathways are known to play a key role in the development and progression of liver fibrosis by promoting the activation of hepatic stellate cells and the production of extracellular matrix proteins such as collagen. Kahweol treatment was also found to decrease the TAA-induced expression of two key profibrotic factors, connective tissue growth factor (CTGF) and transforming growth factor beta (TGF-β), which are known to be involved in the development and progression of liver fibrosis (Wang et al. 2011). By inhibiting the activation of these signaling pathways and the expression of these profibrotic factors, kahweol may help to prevent the development and progression of hepatic fibrosis (Seo et al. 2017).

The combined treatment of kahweol and cafestol has been reported to exhibit chemoprotective effects against the carcinogens such as N-nitrosodimethylamine (NDMA) and 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP) (Majer et al. 2005; Huber et al. 2008). This effect was achieved through the activation of glutathione-S-transferase (GST), the inhibition of sulfotransferase involved in the activation of the amines, and the induction of UDP-glucuronosyltransferase (UGT), which detoxifies the DNA-reactive metabolites of PhIP (Majer et al. 2005). Moreover, kahweol and cafestol inhibited the hepatic carcinogen-activating CYP450s and sulfotransferase. This inhibitory effect was not observed with coffee drinking, in part due to the relatively low contents of kahweol and cafestol present in coffee (Huber et al. 2008). It was also reported that kahweol and cafestol could reduce oxidative hepatotoxicity induced by PhIP, a heterocyclic amine carcinogen, and n-tert-butyl hydroperoxide. This effect was attributed to their ability to reduce the activity of N-acetyltransferase and enhance the detoxification ability through GSH-related mechanisms, as reflected by increases in overall GST activity, several GST subunits, and GSH levels (Huber et al. 2004; Choi et al. 2006). Kahweol and cafestol stimulated the repair protein O6-methylguanine-DNA methyltransferase (MGMT), which plays an important role in repairing DNA damage caused by O6-methylguanine-producing environmental and nutritional carcinogens such as nitrosamines. This stimulation of MGMT by kahweol and cafestol added new perspectives to their antimutagenic/anticarcinogenic potential (Huber et al. 2003). It was reported that HCC, commonly caused by chronic hepatitis C, chronic hepatitis B, alcohol liver disease, and NAFLD, was ameliorated by kahweol treatment through inhibiting the activity of p-Src, p-mTOR, and p-STAT3, which are involved in cancer cell growth, proliferation, and survival (Seo et al. 2021).

Kahweol, cafestol palmitate, and kahweol palmitate were also reported to have anti-angiogenic effects through inhibition of angiogenic processes, including endothelial cell proliferation, migration, invasion, and tube formation (Cárdenas et al. 2011) by inhibiting VEGFR-2 expression and Akt activity without affecting Erk (Moeenfard et al. 2016) or by suppressing STAT3-mediated transcription of MMP and VEGF genes (Kim et al. 2012).

As reviewed so far, both kahweol and cafestol have a range of beneficial effects including antioxidant, anti-inflammatory, anti-fibrotic, and anti-angiogenic properties, and improvement of oxidative hepatotoxicity. These effects may have therapeutic benefits not only for liver diseases but also for various other types of diseases (Fig. 3).

Figure 3.Effects of kahweol and cafestol on liver diseases. Kahweol and cafestol have antioxidant, anti-inflammatory, anti-fibrotic, and anti-carcinogenic effects. CTGF, connective tissue growth factor; CYP1A2, cytochrome P-450 1A2; GST, glutathione-S-transferase; IL-1, interleukin-1; IL-6, interleukin-6; NF-κB, nuclear factor-κB; PPARγ, peroxisome proliferator-activated receptor γ; ROS, reactive oxygen species; TNF-α, tumor necrosis factor-α; TGF-β, transforming growth factor beta.

Chlorogenic acids

Chlorogenic acids (Fig. 1D-1F) are formed by the esterification of quinic acid with various hydroxycinnamic acids, including caffeic acid, ferulic acid, and p-coumaric acid (Clifford et al. 2003). Chlorogenic acids are a type of polyphenol ester commonly found in coffee as well as in other plant-based foods such as fruits, vegetables, and grains (Santana-Gálvez et al. 2017). Chlorogenic acids have been associated with various potential health benefits, including antioxidant (Xu et al. 2012) and anti-inflammatory effects (Hwang et al. 2014; Bisht et al. 2020), and may also have a role in regulating glucose and lipid metabolism (Meng et al. 2013). The antioxidant effect of chlorogenic acid has been demonstrated in alcohol-induced liver injury (Kim et al. 2018). Chlorogenic acid reduced alcohol-induced steatosis, apoptosis, and fibrosis by reducing oxidative stress (Kim et al. 2018). The anti-inflammatory effect of chlorogenic acid in LPS-stimulated RAW 264.7 cells was achieved through inhibition of NO production, COX-2 and iNOS expression, pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6, and NF-κB nuclear translocation (Hwang et al. 2014). It was recently reported that chlorogenic acid protected HFD-induced steatosis and inflammation in the liver through the regulation of gut microbiota and an increase of glucagon-like peptide 1 (GLP-1) secretion (Shi et al. 2021). These studies suggest the potential of chlorogenic acid as s therapeutic agent for treating liver diseases (Fig. 4), but more research is needed to fully understand the mechanisms by which chlorogenic acids may impact human health.

Figure 4.Effect of chlorogenic acids on liver diseases. Chlorogenic acids have antioxidant and anti-inflammatory effects. COX-2, cyclooxygenase-2; GLP-1, Glucagon-like peptide-1; IL-6, interleukin-6; iNOS, inducible nitric oxide synthase; NF-κB, nuclear factor-κB; NO, nitric oxide; ROS, reactive oxygen species; TNF-α, tumor necrosis factor-α.

Melanoidins

Melanoidins (Fig. 1G) are high molecular weight brown pigments formed during the combining reaction of sugars and amino acids under certain conditions such as heating, called the Maillard reaction, a non-enzymatic browning reaction. The empirical formula of melanoidin is C17-18H26-27O10N (Fig. 1G) with 5-40 kDA of molecular weight, but there is currently insufficient data to fully determine the structural properties of melanoidin (Suwannahong et al. 2021). Melanoidins are found in various foods, including coffee, bread, and beer. Coffee melanoidins are formed during the roasting process as coffee bean components undergo structural changes (Moreira et al. 2012; Suwannahong et al. 2021). Coffee melanoidins have been reported to possess antioxidant, antimicrobial, anticariogenic, anti-inflammatory, antihypertensive, and antiglycative activities (Moreira et al. 2012; Choi et al. 2018; Duangjai et al. 2021; Petronilho et al. 2022). Recent research has shown a growing interest in the potential health benefits of melanoidins, particularly in the context of liver disease. Some studies have suggested that melanoidins may have hepatoprotective effects and could help prevent or alleviate liver damage caused by various insults, such as alcohol, oxidative stress, and inflammation (Choi et al. 2018; Li et al. 2021). For example, one study found that melanoidins extracted from coffee had a protective effect against alcohol-induced liver injury in mouse macrophage cells (Li et al. 2021). The authors suggested that this effect was due to the antioxidant and anti-inflammatory properties of melanoidins by reversing alcohol-induced decreases in SIRT1 and SIRT3 transcription, translation, and activation, as well as the nicotinamide adenine dinucleotide levels (Li et al. 2021). Another study investigated the effects of melanoidins from bread crust on liver fibrosis in mice (Wächter et al. 2022). The results showed that treatment with the melanoidins led to a reduction in liver fibrosis, as well as a decrease in markers of oxidative stress and inflammation (Wächter et al. 2022). While these studies suggest that melanoidins may have potential as a therapeutic or preventive agent for liver disease (Fig. 5), more research is needed to fully understand the mechanisms underlying their effects and to determine their safety and efficacy in humans.

Figure 5.Effect of melanoidins on liver diseases. Melanoidins have antioxidant and anti-inflammatory effects. Gpx1, glutathione peroxidase; IL-1β, interleukin-1β; IL-6, interleukin-6; Nfe2l2, nuclear factor E2-related factor 2; ROS, reactive oxygen species; Sod1, superoxide dismutase 1; TNF-α, tumor necrosis factor-α.

Numerous meta-analyses have consistently reported the beneficial effects of coffee consumption on human health. These benefits include a reduction of oxidative damage (Tan et al. 2021; Zheng et al. 2022), an increase in telomere length (Cardin et al. 2013), and activation proteins involved in cell protection (Wahl et al. 2017; Kolb et al. 2020; Karabegović et al. 2021). Moreover, coffee consumption has been associated with a decrease in inflammatory responses (Jones et al. 2010; Aleksandrova et al. 2015; Kolb et al. 2020; Tan et al. 2021; Zheng et al. 2022), and collagen synthesis (Cardin et al. 2013; Ebadi et al. 2021). The anti-inflammatory and antioxidant properties of coffee consumption may also help reduce the risk of NAFLD, hepatic fibrosis (Ebadi et al. 2021; Tan et al. 2021), and hepatocellular carcinoma (Barré et al. 2022; Zheng et al. 2022), although conflicting results have been reported in some cohort studies.

The beneficial properties of coffee components, including caffeine, kahweol, cafestol, chlorogenic acids, and melanoidins, have been shown to ameliorate liver damage and prevent liver diseases such as hepatitis, liver fibrosis, and liver cancer. These components also play a role in regulating metabolic signaling, as coffee components can influence lipid and cancer metabolism by regulating adipogenesis and carcinogenesis (Acheson et al. 1980; Astrup et al. 1990; Huber et al. 2003; Majer et al. 2005; Lee et al. 2007; Moreira et al. 2012; Meng et al. 2013; Perera et al. 2013; Seo et al. 2021; Lebeau et al. 2022). Interestingly, coffee and its components are currently being evaluated in clinical trials for the treatment of liver diseases. For instance, caffeine and chlorogenic acid are under clinical trial against hepatic steatosis and fibrosis in NAFLD with Type 2 diabetes (NCT02929901). Caffeine is also being evaluated as a therapy for fructose-induced hepatic steatosis (NCT00827450), NASH (NCT03432377), and chronic hepatitis C virus-related hepatitis (NCT01572103). While kahweol, cafestol, and melanoidins have not yet been approved or undergone clinical trials for liver diseases, further research in this area may reveal their potential therapeutic benefits.

It is essential to consider the potential effects of coffee on lipid metabolism and metabolic syndrome, especially for patients with liver diseases such as NAFLD. The clinical trial NCT00377975 investigated the effects of coffee consumption on lipid metabolism and suggested that coffee has implications for the management of lipid metabolism in liver disease patients. Moreover, the coffee extract has demonstrated a positive influence on metabolic syndrome markers such as blood pressure, blood glucose, insulin resistance, and blood lipids (NCT02764957). Thus, we propose that coffee consumption or its components could be a therapeutic option for treating liver diseases by regulating their pathological effects. However, while numerous studies have reported positive effects of coffee on health, some studies have shown harmful effects. The exact reasons for the seemingly contradictory findings regarding the effects of coffee on health are not clear, but may be due to factors such as the type of coffee consumed, the method of preparation, its density, additives, and the various components of coffee (Baspinar et al. 2017). Moreover, the effects of coffee may be influenced by the consumer’s health status, including the presence of underlying medical conditions or comorbidities, which can make it challenging to clarify its effects. Therefore, further studies should consider the optimal types and amounts of coffee consumption as well as the management of the participants’ condition. These studies will be crucial in fully understanding and utilizing the therapeutic effects of coffee components for the prevention and treatment of liver diseases.

Overall, we suggest that coffee may prove to be a valuable therapeutic option for those suffering from liver diseases. Coffee-based therapies can help develop affordable drugs optimized for liver health. Synergistic effects should also be taken into account when using coffee with other interventions such as dietary changes, exercise, or medication.

This research was supported by Korea Basic Science Institute (National research Facilities and Equipment Center) grant funded by the Ministry of Education, Republic of Korea (2021R1A6C101A442).

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Article

Review

DTT 2023; 2(2): 133-144

Published online September 30, 2023 https://doi.org/10.58502/DTT.23.0012

Copyright © The Pharmaceutical Society of Korea.

Roles of Coffee and Its Components in Liver Diseases

Eun Seon Pak , Seojeong Park , Hyeri Yoon, Seojeong Kim , Youngjoo Kwon

College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Korea

Correspondence to:Youngjoo Kwon, ykwon@ewha.ac.kr

Received: April 4, 2023; Revised: May 30, 2023; Accepted: June 7, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ((http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Coffee is a widely consumed beverage with multifaceted health benefits. While several studies have explored its effects on various diseases, limited reports have investigated its association with liver disease. Therefore, this review aimed to explore the effects of coffee consumption and its major coffee components on liver disease. Meta-analysis results have suggested that coffee consumption may reduce the risk of non-alcoholic fatty liver disease, hepatic fibrosis, and hepatocellular carcinoma, but the molecular mechanisms underlying these beneficial actions of coffee consumption remain elusive. Studying the individual components of coffee could help us better understand the mechanisms behind its liver protective effects. To clarify a more precise mechanism of coffee-related liver protective effects, the experimentally determined effects of each coffee component on liver diseases are also reviewed.

Keywords: non-alcoholic fatty liver disease (NAFLD), hepatic fibrosis, hepatocellular carcinoma, coffee, kahweol, cafestol

Introduction

Coffee, one of the most widely consumed beverages worldwide, has been extensively studied for its multifaceted effects on human health. Several meta-analyses suggest a non-linear association between coffee consumption and health outcomes. Compared to not drinking coffee, moderate coffee consumption (1-2 cups, 2-3 cups, or 3-5 cups per day, with slight variations between studies) is beneficial in reducing the risk of all-cause mortality, heart failure, and cardiovascular diseases (Ding et al. 2014; Poole et al. 2017; Stevens et al. 2021; Chieng et al. 2022). In addition, cohort studies have shown that moderate coffee consumption, alone or combined with tea, is linked to a lower risk of stroke, dementia, and post-stroke dementia (Chan et al. 2021; Zhang et al. 2021). Another prospective cohort study found that moderate coffee consumption reduced the hazard ratio for coronary heart disease, but showed no significant association with cancer mortality or stroke (Shahinfar et al. 2021). Heavy coffee drinkers appear to have a lower risk of certain cancers, including oral and liver cancers, as well as diseases affecting the nervous system, metabolism, and liver, compared to light coffee drinkers (Poole et al. 2017).

In contrast to the above studies, excessive coffee consumption (> 6 cups per day) has been associated with a modest increase in the risk of cardiovascular disease (Zhou and Hyppönen 2019). In addition, coffee consumption is not recommended for pregnant women or women at high risk of fractures (Poole et al. 2017). These conflicting findings highlight the need for further research to establish a definitive association between coffee consumption and specific diseases, taking into account variables such as the participants’ medical history, the type of coffee consumed, drinking patterns with and without additives such as sugar or milk, and other relevant parameters specific to each disease. Although numerous cohort studies or review papers have suggested that coffee consumption is beneficial for cardiovascular diseases (Ding et al. 2014; Poole et al. 2017; Zhou and Hyppönen 2019; Shahinfar et al. 2021; Stevens et al. 2021; Chieng et al. 2022), few reports have explored the relationship between coffee consumption and liver diseases.

Here, this paper specifically aims to review the effects of coffee consumption and major components of coffee, such as caffeine, cafestol, kahweol, and chlorogenic acids, on liver diseases.

Cohort Studies Showing Effects of Coffee Consumption on Chronic Liver Diseases

After conducting a literature search on PubMed using the search term “coffee, cohort study, and liver disease” for the past 10 years up to February 2023, we were able to identify 70 relevant papers. Some papers investigated the relationship between liver diseases and dietary patterns, including the consumption of alcohol, coffee, and tea, types of alcoholic beverages, smoking, sleep duration, and more (Kaenkumchorn et al. 2021; Mikolasevic et al. 2021; Doustmohammadian et al. 2022). We focused on papers reporting an association between coffee consumption and liver disease to extract more precise information about the effects of coffee on liver diseases.

It has been observed in patients with chronic hepatitis C that consuming 3-5 cups of coffee per day was associated with a reduction in oxidative damage, an increase in telomere length, and a decrease in apoptotic cell death. Additionally, coffee consumption has been shown to reduce collagen synthesis, which is a factor that mediates the protection exerted by coffee against liver disease progression (Cardin et al. 2013). A Meta-analysis of case-control studies and cohort studies suggested a potential inverse association between coffee consumption and the incidence and progression of liver cancer and cirrhosis (Bravi et al. 2013; Sang et al. 2013; Petrick et al. 2015; Setiawan et al. 2015; Kennedy et al. 2016; Wang et al. 2016; Alicandro et al. 2017; Bravi et al. 2017; Godos et al. 2017; Kennedy et al. 2017; Tamura et al. 2018; Tran et al. 2019; Wiltberger et al. 2019; Bhurwal et al. 2020; Di Maso et al. 2021; Kennedy et al. 2021; Kim et al. 2021). Recent cohort studies found that coffee consumption may help reduce the risk of non-alcoholic fatty liver disease (NAFLD), hepatic fibrosis, and hepatocellular carcinoma (HCC) through inhibition of inflammation and oxidative stress (Tan et al. 2021; Barré et al. 2022; Zheng et al. 2022). In addition, coffee consumption alters the composition of the duodenal microbiome in cirrhosis, suggesting that this may contribute to health benefits (Bajaj et al. 2018; Hussain et al. 2020). Interestingly, another meta-analysis showed no association between coffee consumption and NAFLD incidence, but a significant association with reduced probability of liver fibrosis (Ebadi et al. 2021). On the other hand, coffee consumption was not associated with liver fibrosis and its progression to HCC in patients with chronic hepatitis B infection (Chen et al. 2019; Brahmania et al. 2020) and not associated with any lower hepatic steatosis in both non-alcoholic and alcoholic liver diseases (Veronese et al. 2018). Due to these conflicting cohort results, it is necessary to analyze cohort results with better managing the number of participants and diverse variables related to liver diseases, or to perform further studies on the mechanism of action.

The molecular mechanisms underlying the beneficial association between coffee consumption and the reduced risk of liver diseases, including fatty liver, HCC, and liver fibrosis, remain elusive. A recent epigenome-wide association study provided that high coffee consumption was associated with lower levels of DNA methylation at cytosine-phosphate guanine (CpG) sites annotated to the AHRR, F2RL3, FLJ43663, HDAC4, GFI1, and PHGDH genes. Among them, further experiments with PHGDH knock-down in liver cells showed that the association between coffee consumption and fatty liver disease could be mediated by PHGDH expression by altering DNA methylation levels at cg14476101 (Karabegović et al. 2021). PHGDH encodes phosphoglycerate dehydrogenase that catalyzes the conversion of 3-phosphoglycerate to 3-phosphohydroxypyruvate, a step in the phosphorylation pathway of serine biosynthesis (Wahl et al. 2017). As a rich source of phenolic phytochemicals, the health-promoting effects of coffee, such as lowering the risk of HCC and cirrhosis, might be attributed to its ability to upregulate proteins involved in cell protection, particularly antioxidant, detoxifying, and repair enzymes, by activating the nuclear factor erythroid 2-related factor-2 (Nrf2) system (Kolb et al. 2020). Coffee consumption has been also shown to have anti-inflammatory effects by downregulating markers such as interleukin-6 (IL-6) (Aleksandrova et al. 2015), chemokine (C-X3-C motif) ligand 1 (CX3CL1) (Jones et al. 2010), chemokine (C-C motif) ligands 4 (CCL4), interferon γ (IFNγ), and fibroblast growth factor 2 (FGF-2) (Loftfield et al. 2015). Various cohort studies have suggested the beneficial effects of coffee consumption on liver diseases, through either altering post-translational modification or inhibiting inflammation, oxidative stress, and fibrosis. Further detailed mechanistic studies of the individual components of coffee are needed to better understand the specific mechanisms underlying the benefits of coffee consumption for liver diseases.

Coffee contains various bioactive compounds such as caffeine, diterpenes, chlorogenic acids, and melanoidins, which may have different effects on liver health (Hu et al. 2019). Unfortunately, cohort studies of each coffee component other than caffeine have not yet been reported. Therefore, the individual effects of coffee components on liver diseases that have been experimentally determined are summarized in the following sections.

Roles of Bioactive Compounds of Coffee in Liver Disease

Caffeine

Caffeine (Fig. 1A), one of the primary components of coffee, contains a purine ring, which chemically resembles adenosine and acts as a non-selective receptor antagonist of adenosine (Eltzschig et al. 2012). Caffeine metabolism occurs mainly by the cytochrome P-450 1A2 (CYP1A2) enzyme present in the liver (Amchin et al. 1999; Kot and Daniel 2008). Thus, caffeine clearance is considered a measure of CYP1A2 activity. Previous studies found that decreased CYP1A2 activity leading to a reduction in caffeine clearance was associated with NAFLD progression (Perera et al. 2013). Furthermore, liver diseases including cirrhosis, hepatitis B, and hepatitis C cause the impaired elimination of caffeine (Desmond et al. 1980; Scott et al. 1988). These studies suggested reduction of caffeine clearance was associated with liver diseases, yet more studies are needed.

Figure 1. Structures of coffee components. (A) Caffeine. (B) Kahweol. (C) Cafestol. (D-F) Chlorogenic acids, formed by the esterification of quinic acid with caffeic acid (D), ferulic acid (E), and p-coumaric acid (F). (G) Basic structure of melanoidins.

Lipid accumulation in the liver is a pathophysiological hallmark of NAFLD (Pei et al. 2020). Interestingly, caffeine has been shown to increase fat oxidation (Acheson et al. 1980) and energy expenditure (Astrup et al. 1990). These effects suggest a potential role of caffeine to enhance lipid metabolism. Inhibition of lipid accumulation of caffeine was associated with the regulation of low-density lipoprotein receptor (LDLR) expression (Lebeau et al. 2022). A recent study showed that caffeine reduced levels of circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) in healthy volunteers (Lebeau et al. 2022). In addition, caffeine-induced increase in the hepatic endoplasmic reticulum (ER) calcium level inhibited the transcriptional activation of sterol regulatory element binding protein 2 (SREBP2), which is responsible for regulating PCSK9 expression, leading to increased LDLR expression and promotion of low-density lipoprotein cholesterol (LDLc) clearance (Lebeau et al. 2022). This effect of caffeine may be one of the mechanisms of action supporting the beneficial effect of coffee consumption on lipid metabolism disorders resulting in cardiovascular and chronic liver disease.

Liver fibrosis is a pathophysiological process characterized by abnormal tissue proliferation, which is caused by non-alcoholic steatohepatitis (NASH) and NAFLD (Aydın and Akçalı 2018). A systematic review and meta-analysis found that regular caffeine intake from coffee was significantly associated with reduced liver fibrosis in NAFLD (Shen et al. 2016). Caffeine consumption, approximately 2 coffee cups per day, alleviated liver fibrosis (Modi et al. 2010). One well-known mechanism by which caffeine exerts anti-fibrotic effects in the liver is through its function as an adenosine receptor antagonist (Chan et al. 2006). Indeed, caffeine blocked adenosine A2A receptor-mediated fibrosis (Chan et al. 2006). Caffeine inhibited liver fibrosis-induced adenosine A2A receptor activation through upregulation of peroxisome proliferator-activated receptor γ (PPARγ) and reduction of SMAD2/3 (Gressner et al. 2008). Caffeine inhibited matrix metalloproteinases (MMPs) secretion and reduced α-smooth muscle actin (α-SMA) in liver fibrosis (Amer et al. 2017). With increasing evidence of the beneficial role of caffeine in liver disease, caffeine may be a potential therapeutic agent for treating liver diseases (Fig. 2).

Figure 2. Effect of caffeine on liver diseases. Caffeine has anti-cholesterol, anti-fibrotic, and anti-lipid accumulation effects. The marker ↓ indicates inhibition, and indicates receptor blocking. CYP1A2, cytochrome P-450 1A2; LDL, low-density lipoprotein; LDLc, low-density lipoprotein cholesterol; PCSK9, proprotein convertase subtilisin/kexin type 9; PPAR γ, peroxisome proliferator-activated receptor γ; SREBP2, sterol regulatory element binding protein 2; α-SMA, α-smooth muscle actin.

Kahweol and cafestol

Kahweol (Fig. 1B) and cafestol (Fig. 1C) are diterpenoid molecules and are structurally similar to each other. Kahweol and cafestol are the major antioxidative components of coffee and have been considered as components responsible for the proposed biological and pharmacological effects of coffee (Ludwig et al. 2014; Ren et al. 2019).

Kahweol has been shown to possess antioxidant and anti-inflammatory properties, making it effective in mitigating acetaminophen-induced liver damage in mice. This was achieved by restoring glutathione content, inhibiting endoplasmic reticulum (ER) stress-induced cell death in hepatocytes, stimulating the Nrf2-dependent cellular defense system, and reducing NK-κB-mediated inflammation (Kim et al. 2022). The ability of kahweol to increase Nrf2 expression was attributed to its reduction of Keap1 protein expression, which occurred independently of p62-dependent autophagy degradation (Seo et al. 2020). Furthermore, kahweol and cafestol exhibited potent hepatoprotective effects against CCl4-induced oxidative stress in mice. These effects were attributed to their ability to inhibit the activity of CYP2E1, thus blocking the bioactivation of CCl4. As a result, the formation of trichloromethyl radicals is decreased, and the antioxidant and free radical-scavenging activities of kahweol and cafestol were able to prevent lipid peroxidation and subsequent hepatocellular injury (Lee et al. 2007). Kahweol reduced the production of several pro-inflammatory cytokines, including IL-1, IL-6, and TNF-α, which are known to be involved in hepatitis, liver fibrosis, and cirrhosis. The inhibitory effect of kahweol on liver inflammation was due to its ability to downregulate the expression of two important transcription factors, phospho-NF-κB and phospho-STAT3 in HCC cells (Seo et al. 2018). These transcription factors are known to play a key role in the activation of inflammatory pathways and are often dysregulated in liver diseases such as hepatitis and liver cancer (Schmidt-Arras and Rose-John 2016; Sultan et al. 2017). Cafestol treatment before inducing hepatic ischemia-reperfusion injury reduced the levels of pro-inflammatory cytokines, markers of apoptosis, and autophagy in the mouse liver tissue. The liver protective effects of cafestol were associated with the suppression of the ERK/PPARγ pathway, which plays a key role in regulating both inflammation and oxidative stress (Han et al. 2016; Ji et al. 2020).

In a study using a thioacetamide (TAA)-induced hepatic fibrosis mouse model, kahweol treatment was found to significantly attenuate liver fibrosis by inhibiting the TAA-induced activation of several signaling pathways, including p-STAT3, pERK, and pJNK (Seo et al. 2017). These signaling pathways are known to play a key role in the development and progression of liver fibrosis by promoting the activation of hepatic stellate cells and the production of extracellular matrix proteins such as collagen. Kahweol treatment was also found to decrease the TAA-induced expression of two key profibrotic factors, connective tissue growth factor (CTGF) and transforming growth factor beta (TGF-β), which are known to be involved in the development and progression of liver fibrosis (Wang et al. 2011). By inhibiting the activation of these signaling pathways and the expression of these profibrotic factors, kahweol may help to prevent the development and progression of hepatic fibrosis (Seo et al. 2017).

The combined treatment of kahweol and cafestol has been reported to exhibit chemoprotective effects against the carcinogens such as N-nitrosodimethylamine (NDMA) and 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP) (Majer et al. 2005; Huber et al. 2008). This effect was achieved through the activation of glutathione-S-transferase (GST), the inhibition of sulfotransferase involved in the activation of the amines, and the induction of UDP-glucuronosyltransferase (UGT), which detoxifies the DNA-reactive metabolites of PhIP (Majer et al. 2005). Moreover, kahweol and cafestol inhibited the hepatic carcinogen-activating CYP450s and sulfotransferase. This inhibitory effect was not observed with coffee drinking, in part due to the relatively low contents of kahweol and cafestol present in coffee (Huber et al. 2008). It was also reported that kahweol and cafestol could reduce oxidative hepatotoxicity induced by PhIP, a heterocyclic amine carcinogen, and n-tert-butyl hydroperoxide. This effect was attributed to their ability to reduce the activity of N-acetyltransferase and enhance the detoxification ability through GSH-related mechanisms, as reflected by increases in overall GST activity, several GST subunits, and GSH levels (Huber et al. 2004; Choi et al. 2006). Kahweol and cafestol stimulated the repair protein O6-methylguanine-DNA methyltransferase (MGMT), which plays an important role in repairing DNA damage caused by O6-methylguanine-producing environmental and nutritional carcinogens such as nitrosamines. This stimulation of MGMT by kahweol and cafestol added new perspectives to their antimutagenic/anticarcinogenic potential (Huber et al. 2003). It was reported that HCC, commonly caused by chronic hepatitis C, chronic hepatitis B, alcohol liver disease, and NAFLD, was ameliorated by kahweol treatment through inhibiting the activity of p-Src, p-mTOR, and p-STAT3, which are involved in cancer cell growth, proliferation, and survival (Seo et al. 2021).

Kahweol, cafestol palmitate, and kahweol palmitate were also reported to have anti-angiogenic effects through inhibition of angiogenic processes, including endothelial cell proliferation, migration, invasion, and tube formation (Cárdenas et al. 2011) by inhibiting VEGFR-2 expression and Akt activity without affecting Erk (Moeenfard et al. 2016) or by suppressing STAT3-mediated transcription of MMP and VEGF genes (Kim et al. 2012).

As reviewed so far, both kahweol and cafestol have a range of beneficial effects including antioxidant, anti-inflammatory, anti-fibrotic, and anti-angiogenic properties, and improvement of oxidative hepatotoxicity. These effects may have therapeutic benefits not only for liver diseases but also for various other types of diseases (Fig. 3).

Figure 3. Effects of kahweol and cafestol on liver diseases. Kahweol and cafestol have antioxidant, anti-inflammatory, anti-fibrotic, and anti-carcinogenic effects. CTGF, connective tissue growth factor; CYP1A2, cytochrome P-450 1A2; GST, glutathione-S-transferase; IL-1, interleukin-1; IL-6, interleukin-6; NF-κB, nuclear factor-κB; PPARγ, peroxisome proliferator-activated receptor γ; ROS, reactive oxygen species; TNF-α, tumor necrosis factor-α; TGF-β, transforming growth factor beta.

Chlorogenic acids

Chlorogenic acids (Fig. 1D-1F) are formed by the esterification of quinic acid with various hydroxycinnamic acids, including caffeic acid, ferulic acid, and p-coumaric acid (Clifford et al. 2003). Chlorogenic acids are a type of polyphenol ester commonly found in coffee as well as in other plant-based foods such as fruits, vegetables, and grains (Santana-Gálvez et al. 2017). Chlorogenic acids have been associated with various potential health benefits, including antioxidant (Xu et al. 2012) and anti-inflammatory effects (Hwang et al. 2014; Bisht et al. 2020), and may also have a role in regulating glucose and lipid metabolism (Meng et al. 2013). The antioxidant effect of chlorogenic acid has been demonstrated in alcohol-induced liver injury (Kim et al. 2018). Chlorogenic acid reduced alcohol-induced steatosis, apoptosis, and fibrosis by reducing oxidative stress (Kim et al. 2018). The anti-inflammatory effect of chlorogenic acid in LPS-stimulated RAW 264.7 cells was achieved through inhibition of NO production, COX-2 and iNOS expression, pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6, and NF-κB nuclear translocation (Hwang et al. 2014). It was recently reported that chlorogenic acid protected HFD-induced steatosis and inflammation in the liver through the regulation of gut microbiota and an increase of glucagon-like peptide 1 (GLP-1) secretion (Shi et al. 2021). These studies suggest the potential of chlorogenic acid as s therapeutic agent for treating liver diseases (Fig. 4), but more research is needed to fully understand the mechanisms by which chlorogenic acids may impact human health.

Figure 4. Effect of chlorogenic acids on liver diseases. Chlorogenic acids have antioxidant and anti-inflammatory effects. COX-2, cyclooxygenase-2; GLP-1, Glucagon-like peptide-1; IL-6, interleukin-6; iNOS, inducible nitric oxide synthase; NF-κB, nuclear factor-κB; NO, nitric oxide; ROS, reactive oxygen species; TNF-α, tumor necrosis factor-α.

Melanoidins

Melanoidins (Fig. 1G) are high molecular weight brown pigments formed during the combining reaction of sugars and amino acids under certain conditions such as heating, called the Maillard reaction, a non-enzymatic browning reaction. The empirical formula of melanoidin is C17-18H26-27O10N (Fig. 1G) with 5-40 kDA of molecular weight, but there is currently insufficient data to fully determine the structural properties of melanoidin (Suwannahong et al. 2021). Melanoidins are found in various foods, including coffee, bread, and beer. Coffee melanoidins are formed during the roasting process as coffee bean components undergo structural changes (Moreira et al. 2012; Suwannahong et al. 2021). Coffee melanoidins have been reported to possess antioxidant, antimicrobial, anticariogenic, anti-inflammatory, antihypertensive, and antiglycative activities (Moreira et al. 2012; Choi et al. 2018; Duangjai et al. 2021; Petronilho et al. 2022). Recent research has shown a growing interest in the potential health benefits of melanoidins, particularly in the context of liver disease. Some studies have suggested that melanoidins may have hepatoprotective effects and could help prevent or alleviate liver damage caused by various insults, such as alcohol, oxidative stress, and inflammation (Choi et al. 2018; Li et al. 2021). For example, one study found that melanoidins extracted from coffee had a protective effect against alcohol-induced liver injury in mouse macrophage cells (Li et al. 2021). The authors suggested that this effect was due to the antioxidant and anti-inflammatory properties of melanoidins by reversing alcohol-induced decreases in SIRT1 and SIRT3 transcription, translation, and activation, as well as the nicotinamide adenine dinucleotide levels (Li et al. 2021). Another study investigated the effects of melanoidins from bread crust on liver fibrosis in mice (Wächter et al. 2022). The results showed that treatment with the melanoidins led to a reduction in liver fibrosis, as well as a decrease in markers of oxidative stress and inflammation (Wächter et al. 2022). While these studies suggest that melanoidins may have potential as a therapeutic or preventive agent for liver disease (Fig. 5), more research is needed to fully understand the mechanisms underlying their effects and to determine their safety and efficacy in humans.

Figure 5. Effect of melanoidins on liver diseases. Melanoidins have antioxidant and anti-inflammatory effects. Gpx1, glutathione peroxidase; IL-1β, interleukin-1β; IL-6, interleukin-6; Nfe2l2, nuclear factor E2-related factor 2; ROS, reactive oxygen species; Sod1, superoxide dismutase 1; TNF-α, tumor necrosis factor-α.

Conclusion

Numerous meta-analyses have consistently reported the beneficial effects of coffee consumption on human health. These benefits include a reduction of oxidative damage (Tan et al. 2021; Zheng et al. 2022), an increase in telomere length (Cardin et al. 2013), and activation proteins involved in cell protection (Wahl et al. 2017; Kolb et al. 2020; Karabegović et al. 2021). Moreover, coffee consumption has been associated with a decrease in inflammatory responses (Jones et al. 2010; Aleksandrova et al. 2015; Kolb et al. 2020; Tan et al. 2021; Zheng et al. 2022), and collagen synthesis (Cardin et al. 2013; Ebadi et al. 2021). The anti-inflammatory and antioxidant properties of coffee consumption may also help reduce the risk of NAFLD, hepatic fibrosis (Ebadi et al. 2021; Tan et al. 2021), and hepatocellular carcinoma (Barré et al. 2022; Zheng et al. 2022), although conflicting results have been reported in some cohort studies.

The beneficial properties of coffee components, including caffeine, kahweol, cafestol, chlorogenic acids, and melanoidins, have been shown to ameliorate liver damage and prevent liver diseases such as hepatitis, liver fibrosis, and liver cancer. These components also play a role in regulating metabolic signaling, as coffee components can influence lipid and cancer metabolism by regulating adipogenesis and carcinogenesis (Acheson et al. 1980; Astrup et al. 1990; Huber et al. 2003; Majer et al. 2005; Lee et al. 2007; Moreira et al. 2012; Meng et al. 2013; Perera et al. 2013; Seo et al. 2021; Lebeau et al. 2022). Interestingly, coffee and its components are currently being evaluated in clinical trials for the treatment of liver diseases. For instance, caffeine and chlorogenic acid are under clinical trial against hepatic steatosis and fibrosis in NAFLD with Type 2 diabetes (NCT02929901). Caffeine is also being evaluated as a therapy for fructose-induced hepatic steatosis (NCT00827450), NASH (NCT03432377), and chronic hepatitis C virus-related hepatitis (NCT01572103). While kahweol, cafestol, and melanoidins have not yet been approved or undergone clinical trials for liver diseases, further research in this area may reveal their potential therapeutic benefits.

It is essential to consider the potential effects of coffee on lipid metabolism and metabolic syndrome, especially for patients with liver diseases such as NAFLD. The clinical trial NCT00377975 investigated the effects of coffee consumption on lipid metabolism and suggested that coffee has implications for the management of lipid metabolism in liver disease patients. Moreover, the coffee extract has demonstrated a positive influence on metabolic syndrome markers such as blood pressure, blood glucose, insulin resistance, and blood lipids (NCT02764957). Thus, we propose that coffee consumption or its components could be a therapeutic option for treating liver diseases by regulating their pathological effects. However, while numerous studies have reported positive effects of coffee on health, some studies have shown harmful effects. The exact reasons for the seemingly contradictory findings regarding the effects of coffee on health are not clear, but may be due to factors such as the type of coffee consumed, the method of preparation, its density, additives, and the various components of coffee (Baspinar et al. 2017). Moreover, the effects of coffee may be influenced by the consumer’s health status, including the presence of underlying medical conditions or comorbidities, which can make it challenging to clarify its effects. Therefore, further studies should consider the optimal types and amounts of coffee consumption as well as the management of the participants’ condition. These studies will be crucial in fully understanding and utilizing the therapeutic effects of coffee components for the prevention and treatment of liver diseases.

Overall, we suggest that coffee may prove to be a valuable therapeutic option for those suffering from liver diseases. Coffee-based therapies can help develop affordable drugs optimized for liver health. Synergistic effects should also be taken into account when using coffee with other interventions such as dietary changes, exercise, or medication.

Acknowledgements

This research was supported by Korea Basic Science Institute (National research Facilities and Equipment Center) grant funded by the Ministry of Education, Republic of Korea (2021R1A6C101A442).

Conflict of interest

The authors declare that they have no conflict of interest.

Fig 1.

Figure 1.Structures of coffee components. (A) Caffeine. (B) Kahweol. (C) Cafestol. (D-F) Chlorogenic acids, formed by the esterification of quinic acid with caffeic acid (D), ferulic acid (E), and p-coumaric acid (F). (G) Basic structure of melanoidins.
Drug Targets and Therapeutics 2023; 2: 133-144https://doi.org/10.58502/DTT.23.0012

Fig 2.

Figure 2.Effect of caffeine on liver diseases. Caffeine has anti-cholesterol, anti-fibrotic, and anti-lipid accumulation effects. The marker ↓ indicates inhibition, and indicates receptor blocking. CYP1A2, cytochrome P-450 1A2; LDL, low-density lipoprotein; LDLc, low-density lipoprotein cholesterol; PCSK9, proprotein convertase subtilisin/kexin type 9; PPAR γ, peroxisome proliferator-activated receptor γ; SREBP2, sterol regulatory element binding protein 2; α-SMA, α-smooth muscle actin.
Drug Targets and Therapeutics 2023; 2: 133-144https://doi.org/10.58502/DTT.23.0012

Fig 3.

Figure 3.Effects of kahweol and cafestol on liver diseases. Kahweol and cafestol have antioxidant, anti-inflammatory, anti-fibrotic, and anti-carcinogenic effects. CTGF, connective tissue growth factor; CYP1A2, cytochrome P-450 1A2; GST, glutathione-S-transferase; IL-1, interleukin-1; IL-6, interleukin-6; NF-κB, nuclear factor-κB; PPARγ, peroxisome proliferator-activated receptor γ; ROS, reactive oxygen species; TNF-α, tumor necrosis factor-α; TGF-β, transforming growth factor beta.
Drug Targets and Therapeutics 2023; 2: 133-144https://doi.org/10.58502/DTT.23.0012

Fig 4.

Figure 4.Effect of chlorogenic acids on liver diseases. Chlorogenic acids have antioxidant and anti-inflammatory effects. COX-2, cyclooxygenase-2; GLP-1, Glucagon-like peptide-1; IL-6, interleukin-6; iNOS, inducible nitric oxide synthase; NF-κB, nuclear factor-κB; NO, nitric oxide; ROS, reactive oxygen species; TNF-α, tumor necrosis factor-α.
Drug Targets and Therapeutics 2023; 2: 133-144https://doi.org/10.58502/DTT.23.0012

Fig 5.

Figure 5.Effect of melanoidins on liver diseases. Melanoidins have antioxidant and anti-inflammatory effects. Gpx1, glutathione peroxidase; IL-1β, interleukin-1β; IL-6, interleukin-6; Nfe2l2, nuclear factor E2-related factor 2; ROS, reactive oxygen species; Sod1, superoxide dismutase 1; TNF-α, tumor necrosis factor-α.
Drug Targets and Therapeutics 2023; 2: 133-144https://doi.org/10.58502/DTT.23.0012

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