Mechanisms by Which Coffee may Reduce Severity of NAFLD
Despite the persuasive epidemiological data, particularly for ultrasound and histological studies, the cellular and molecular mechanisms underlying the effects of coffee consumption in patients with NAFLD remain undefined. Antioxidant, anti-inflammatory, antifibrotic, and altered energy metabolism have been potentially implicated.
Prior to examining these possible effects of coffee on NAFLD, a consideration of coffee constituents is important. The basic chemical composition of coffee depends on its species and physiological aspects. The main bioactive compounds and their effects on liver disease are listed in Table 2 and have been reviewed.[24,27–35]
Coffee and T2DM
Individuals with T2DM have higher incidence of NAFLD, while NAFLD exacerbates hepatic insulin resistance and increases the risk of developing T2DM.[36,37] To date, systematic reviews and meta-analysis have indicated that higher coffee consumption is consistently associated with a lower risk of T2DM. This association does not depend on race, gender, geographic distribution of the study populations, or the type of coffee consumed.[38–41] The mechanism(s) for this strong protective effect of coffee on T2DM is still needed to be elucidated. High coffee consumption was associated with greater insulin sensitivity in several but not all cross-sectional studies.[40] Increased plasma adiponectin, antioxidation, anti-inflammation, and thermogenic effect of coffee may contribute to the lower risk of T2DM.[41,42]
Coffee and Oxidative Injury
Of interest, there have been several studies which indicate that coffee consumption is inversely related to the incidence of diseases in which reactive oxygen species (ROS) are involved. It is postulated that the antioxidant properties of coffee may account for this phenomenon. Vitaglione et al.[34] established a high-fat-diet (HFD)-induced non-alcoholic steatohepatitis (NASH) model in male Wistar rats to study the protective mechanisms of coffee, or its component polyphenols or melanoidins against NAFLD. Biomarkers of antioxidant status measured in both serum and liver samples show that HFD-fed rats had significantly higher concentrations of oxidized glutathione (GSSG) than control rats. Coffee, polyphenols, or melanoidins reduced GSSG concentrations in HFD-fed rats supplemented with coffee in their drinking water compared with those given water only. Likewise, serum malondialdehyde concentration was significantly higher in rats in the HFD group than in control rats (2.03 ± 0.14 μM vs 1.47 ± 0.12 μM). Coffee consumption (1.50 ± 0.09 μM) or polyphenols (1.62 ± 0.08 μM) returned these levels to control values. Further, there was a significant increase in antioxidant capacity in rats treated with polyphenols in drinking water compared with controls (0.36 ± 0.02 mM Trolox® equivalent [TE] vs 0.32 ± 0.01 mM TE).[34]
Goya L et al. investigated the potential protective effect of coffee melanoidins, in particular, a water-soluble high-molecular weight fraction, on the redox status of cultured human HCC, HepG2 cells. The results show that coffee melanoidins conferred significant protection against oxidative insults.[35]
To establish whether coffee consumption protects humans against oxidative DNA damage, a cross-over intervention study was conducted. In this trial, 38 participants consumed 800 mL coffee (or water in controls) daily over 5 days. DNA damage was measured in peripheral lymphocytes. The extent of DNA migration attributable to formation of oxidized purines (also known as formamidopyrimidine glycosylase sensitive sites) was decreased by 12% after coffee intake (P = 0.006). These findings suggest that coffee consumption prevents endogenous formation of oxidative DNA damage in humans. While this observation may be causally related to the beneficial health effects of coffee, biochemical indices of redox status such as malondialdehyde, 3-nitrotyrosine and total antioxidant levels in plasma, glutathione concentrations in blood, intracellular ROS levels, and the activities of superoxide dismutase and glutathione peroxidase in lymphocytes were not markedly altered at the end of the trial.[43]
Investigators have observed different levels of oxidative DNA damage and DNA repair in the livers of coffee-fed mice.[44] In one study, lean male mice were fed 0.1% (w/v) instant coffee solution prepared weekly with 60°C tap water. At 2, 4, and 8 months, there was no difference in the hepatic levels of 8-hydroxydeoxyguanosine (8-OH-dG, a marker of oxidative DNA damage) and 8-OH-dG repair-associated genes, redox system-associated genes, and hepatic lipoperoxide levels between the coffee-fed and control groups of mice. These results suggest that instant coffee consumption has little, if any, effect on hepatic oxidative stress in lean mice. Similarly, others report little or no significant difference in catalase (0.2 ± 0.7 vs 0.3 ± 0.7 nM/min/mL) levels, superoxide dismutase (4.7 ± 2.1 vs 5.4 ± 3.4 U/mL), or thiobarbituric acid-reactive substances (3.9 ± 1.5 vs 4.0 ± 1.8 μM/mL) between NAFLD and controls. Hence, while coffee intake has a protective effect against severity of NAFLD, the weight of evidence (albeit, currently incomplete) is that coffee's positive effects are unlikely to be attributable to any differences in antioxidant variables.[26]
Coffee and Liver Inflammation
Coffee intake has been associated with reduced levels of abnormalities in serum aspartate aminotransferase (AST), ALT,[45–47] and GGT.[48] Fukushima Y et al.[49] conducted a study where mice were fed HFD to induce NAFLD, then treated with or without coffee (1.1% decaffeinated/caffeine-containing instant coffee). Mesenteric fat weight was lower in the HFD+coffee group than those fed a HFD without coffee (P < 0.05). Further, serum AST and ALT levels were significantly lower in the HFD+coffee group than in mice fed a HFD only (P < 0.05). Pro-inflammatory interleukin-1beta (IL-1β) gene expression in murine liver was upregulated in the HFD group and was significantly downregulated by coffee consumption (P < 0.01). Expression of monocyte chemoattractant protein-1 in liver and adipose was also suppressed in the HFD+coffee group. Hence, coffee consumption appears to significantly reduce hepatic pro-inflammatory response.
In a separate study, co-administration of coffee with a HFD in rodents appeared to reduce tumor necrosis factor-α (TNF-α), tissue transglutaminase, and transforming growth factor β (TGF-β) expression in the liver, and increased expression of adiponectin receptor and peroxisome proliferator-activated receptor α. Coffee also lowered hepatic concentrations of TNF-α, interferon-γ and increased anti-inflammatory cytokines, IL-4, and IL-10.[34]
Coffee and Hepatic Fibrosis
Few studies have discussed the influence of coffee on liver fibrosis in NAFLD. In a recent European study, 195 morbidly obese patients referred for bariatric surgery were assessed.[50] Liver biopsies showed NASH in 19%, and significant fibrosis in 35%. By logistic regression analysis, regular coffee intake was an independent factor negatively associated with significant fibrosis in a model that included AST, HOMA-IR, presence of the metabolic syndrome, and NASH. Interestingly, the consumption of regular coffee (but not espresso) was associated with an earlier stage of fibrosis and was independently protective against fibrosis.[50] Sucrose, which is composed of glucose and fructose, is often added by espresso consumers to their coffee and the authors noted that this may have potentially countered coffee's positive effects in this study, particularly by the potential detrimental effect of fructose on NAFLD. Thus, fructose consumption has been noted to aggravate the severity of liver fibrosis in North American patients who have NASH.[51,52]
Few studies have addressed the mechanism for the possible anti-fibrotic effects of coffee on liver fibrosis in NAFLD. In NASH-associated fibrosis, the principal cell type responsible for extracellular matrix production is the hepatic stellate cell.[53] The mechanisms of fibrogenesis in the liver are dependent on an interplay of many pro-fibrotic and anti-fibrotic cytokines and growth factors. TGF-β is one such pro-fibrogenic growth factor. In turn, TGF-β can activate connective tissue growth factor (CTGF) which is also responsive to insulin and other metabolic factors in NAFLD, and which can also mediate matrix production.[54] Caffeine inhibits CTGF synthesis in hepatocytes and liver non-parenchymal cells, primarily by inducing degradation of Smad2, thereby interrupting TGF-β signaling.[55]
Coffee and Hepatic Metabolism
The liver plays diverse and crucial roles in lipogenesis, gluconeogenesis, and cholesterol metabolism.[37] In a rodent model that develops metabolic syndrome and NAFLD when fed a high-carbohydrate, HFD, supplementation with Colombian coffee extract improved glucose tolerance, decreased hypertension, induced cardiovascular remodeling, and attenuated NAFLD severity. Of note, these changes were not associated with weight loss or reduction of serum lipids in the animals.[56] Interestingly, one study reported that some coffee brewing techniques raise serum total and low-density-lipoprotein cholesterol concentrations in humans.[29] The diterpene lipids, cafestol, and kahweol (also main constituents of coffee) were considered to be the responsible lipid-altering factors. In contrast, filtered coffee does not appear to affect serum cholesterol, and this is thought to be related to the removal of diterpenes by the filtration process (filter paper).[29]
Adiponectin is an adipokine that governs insulin sensitivity and has potent anti-inflammatory effects. Plasma adiponectin levels are often lower in patients with NAFLD, and correlate inversely with the severity of steatosis and NASH. In a cross-sectional study comprised of 2554 male and 763 female Japanese workers, associations between coffee consumption and adiponectin, leptin, markers for subclinical inflammation, glucose metabolism, lipids, and liver enzymes were ascertained. The findings revealed that coffee consumption was associated with higher serum adiponectin and lower serum leptin levels.[57]
Coffee is also enriched with polyphenols (coffee polyphenols, CPP). The effects of CPP on diet-induced body fat accumulation was investigated, and C57BL/6J mice were fed either a control diet, HFD, or HFD supplemented with 0.5–1.0% CPP for 2–15 weeks. Supplementation of a HFD with CPP significantly reduced body weight gain, abdominal and liver fat accumulation, as well macrophage infiltration into adipose. Energy expenditure, evaluated by indirect calorimetry, was significantly increased in CPP-fed mice. The hepatic transcript levels of sterol regulatory element-binding protein (SREBP)-1c, acetyl-CoA carboxylase-1 and -2, stearoyl-CoA desaturase-1, and pyruvate dehydrogenase kinase-4 were also significantly reduced in CPP-fed mice compared with HFD mice. CPP has also been shown to suppress the expression of SREBP-1c in Hepa 1–6 cells, with a concomitant increase in microRNA (miR)-122. Structure–activity relationship studies of nine quinic acid derivatives isolated from CPP in Hepa 1–6 cells also suggest that mono- or di-caffeoylquinic acids may have potent and potentially beneficial effects.[33] Thus, it appears that CPP enhances energy metabolism, reduces lipogenesis by downregulating SREBP-1c and related signaling pathways, thereby suppressing the accumulation of body fat and newly synthesized (saturated) fatty acids in the liver.[33]
J Gastroenterol Hepatol. 2014;29(3):435-441. © 2014 Blackwell Publishing
