Coffee Restores Expression of lncRNAs Involved in Steatosis and Fibrosis in a Mouse Model of NAFLD

Background and aim: Coffee intake exerts protective effects against non-alcoholic fatty liver disease (NAFLD), although without fully cleared mechanisms. In this study we aimed to assess whether coffee consumption may influence the expression of long non-coding RNAs (lncRNAs) in the liver. Methods: C57BL/6J mice were fed a 12-week standard diet (SD), high-fat diet (HFD) or HFD plus decaffeinated coffee solution (HFD + coffee). Expression of specific lncRNAs involved in NAFLD was analyzed by real-time PCR. For the most differentially expressed lncRNAs, the analysis was also extended to their mRNA targets. Results: Decaffeinated coffee intake reduced body weight gain, prevented NAFLD, lowered hyperglycemia and hypercholesterolemia. NAFLD was associated with lower hepatic expression of Gm16551, a lncRNA inhibiting de novo lipogenesis, and higher expression of H19, a lncRNA promoting fibrogenesis. Coffee intake restored Gm16551 to levels observed in lean mice and downregulated gene expression of its targets acetyl coenzyme A carboxylase 1 and stearoyl coenzyme A desaturase 1. Furthermore, coffee consumption markedly decreased hepatic expression of H19 and of its target gene collagen alpha-1(I) chain; consistently, in mice fed HFD + coffee liver expression of αSMA protein returned to levels of mice fed SD. Expression of lncRNA involved in circadian clock such as fatty liver-related lncRNA 1 (FLRL1) and fatty liver-related lncRNA 2 (FLRL2) were upregulated by HFD and were also modulated by coffee intake. Conclusion. Hepatoprotective effects of coffee may be depending on the modulation of lncRNAs involved in key pathways of NAFLD onset and progression.

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Coffee prevents fatty liver disease induced by a high-fat diet by modulating pathways of the gut–liver axis

Journal of Nutritional Science ◽

10.1017/jns.2019.10 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 10

Author(s):

Paola Vitaglione ◽

Giovanna Mazzone ◽

Vincenzo Lembo ◽

Giuseppe D'Argenio ◽

Antonella Rossi ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

High Fat Diet ◽

Fatty Liver Disease ◽

Coffee Consumption ◽

Liver Fat ◽

Standard Diet ◽

High Fat ◽

Metabolic Derangement ◽

Alcoholic Fatty Liver

AbstractCoffee consumption is inversely associated with the risk of non-alcoholic fatty liver disease (NAFLD). A gap in the literature still exists concerning the intestinal mechanisms that are involved in the protective effect of coffee consumption towards NAFLD. In this study, twenty-four C57BL/6J mice were divided into three groups each receiving a standard diet, a high-fat diet (HFD) or an HFD plus decaffeinated coffee (HFD+COFFEE) for 12 weeks. Coffee supplementation reduced HFD-induced liver macrovesicular steatosis (P < 0·01) and serum cholesterol (P < 0·001), alanine aminotransferase and glucose (P < 0·05). Accordingly, liver PPAR- α (P < 0·05) and acyl-CoA oxidase-1 (P < 0·05) as well as duodenal ATP-binding cassette (ABC) subfamily A1 (ABCA1) and subfamily G1 (ABCG1) (P < 0·05) mRNA expressions increased with coffee consumption. Compared with HFD animals, HFD+COFFEE mice had more undigested lipids in the caecal content and higher free fatty acid receptor-1 mRNA expression in the duodenum and colon. Furthermore, they showed an up-regulation of duodenal and colonic zonulin-1 (P < 0·05), duodenal claudin (P < 0·05) and duodenal peptide YY (P < 0·05) mRNA as well as a higher abundance of Alcaligenaceae in the faeces (P < 0·05). HFD+COFFEE mice had an energy intake comparable with HFD-fed mice but starting from the eighth intervention week they gained significantly less weight over time. Data altogether showed that coffee supplementation prevented HFD-induced NAFLD in mice by reducing hepatic fat deposition and metabolic derangement through modification of pathways underpinning liver fat oxidation, intestinal cholesterol efflux, energy metabolism and gut permeability. The hepatic and metabolic benefits induced by coffee were accompanied by changes in the gut microbiota.

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Coffee consumption and risk of renal cell carcinoma in the NIH-AARP Diet and Health Study

International Journal of Epidemiology ◽

10.1093/ije/dyab011 ◽

2021 ◽

Author(s):

Jongeun Rhee ◽

Erikka Loftfield ◽

Neal D Freedman ◽

Linda M Liao ◽

Rashmi Sinha ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Cox Regression ◽

Coffee Consumption ◽

Health Study ◽

Coffee Intake ◽

Decaffeinated Coffee ◽

Incident Cases ◽

Reduced Risk

Abstract Background Coffee consumption has been associated with a reduced risk of some cancers, but the evidence for renal cell carcinoma (RCC) is inconclusive. We investigated the relationship between coffee and RCC within a large cohort. Methods Coffee intake was assessed at baseline in the National Institutes of Health–American Association of Retired Persons Diet and Health Study. Among 420 118 participants eligible for analysis, 2674 incident cases were identified. We fitted Cox-regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for coffee consumption vs non-drinkers. Results We observed HRs of 0.94 (95% CI 0.81, 1.09), 0.94 (0.81, 1.09), 0.80 (0.70, 0.92) and 0.77 (0.66, 0.90) for usual coffee intake of <1, 1, 2–3 and ≥4 cups/day, respectively (Ptrend = 0.00003). This relationship was observed among never-smokers (≥4 cups/day: HR 0.62, 95% CI 0.46, 0.83; Ptrend = 0.000003) but not ever-smokers (HR 0.85, 95% CI 0.70, 1.05; Ptrend = 0.35; Pinteraction = 0.0009) and remained in analyses restricted to cases diagnosed >10 years after baseline (HR 0.65, 95% CI 0.51, 0.82; Ptrend = 0.0005). Associations were similar between subgroups who drank predominately caffeinated or decaffeinated coffee (Pinteraction = 0.74). Conclusion In this investigation of coffee and RCC, to our knowledge the largest to date, we observed a 20% reduced risk for intake of ≥2 cups/day vs not drinking. Our findings add RCC to the growing list of cancers for which coffee consumption may be protective.

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Role of Insulin Resistance in MAFLD

International Journal of Molecular Sciences ◽

10.3390/ijms22084156 ◽

2021 ◽

Vol 22 (8) ◽

pp. 4156

Author(s):

Yoshitaka Sakurai ◽

Naoto Kubota ◽

Toshimasa Yamauchi ◽

Takashi Kadowaki

Keyword(s):

Insulin Resistance ◽

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

De Novo Lipogenesis ◽

Hepatic Insulin Resistance ◽

Metabolic Dysfunction ◽

Alcoholic Fatty Liver ◽

Fat Accumulation

Many studies have reported that metabolic dysfunction is closely involved in the complex mechanism underlying the development of non-alcoholic fatty liver disease (NAFLD), which has prompted a movement to consider renaming NAFLD as metabolic dysfunction-associated fatty liver disease (MAFLD). Metabolic dysfunction in this context encompasses obesity, type 2 diabetes mellitus, hypertension, dyslipidemia, and metabolic syndrome, with insulin resistance as the common underlying pathophysiology. Imbalance between energy intake and expenditure results in insulin resistance in various tissues and alteration of the gut microbiota, resulting in fat accumulation in the liver. The role of genetics has also been revealed in hepatic fat accumulation and fibrosis. In the process of fat accumulation in the liver, intracellular damage as well as hepatic insulin resistance further potentiates inflammation, fibrosis, and carcinogenesis. Increased lipogenic substrate supply from other tissues, hepatic zonation of Irs1, and other factors, including ER stress, play crucial roles in increased hepatic de novo lipogenesis in MAFLD with hepatic insulin resistance. Herein, we provide an overview of the factors contributing to and the role of systemic and local insulin resistance in the development and progression of MAFLD.

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High-fructose feeding does not induce steatosis or non-alcoholic fatty liver disease in pigs

Scientific Reports ◽

10.1038/s41598-021-82208-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Nikolaj H. Schmidt ◽

Pia Svendsen ◽

Julián Albarrán-Juárez ◽

Søren K. Moestrup ◽

Jacob Fog Bentzon

Keyword(s):

Adipose Tissue ◽

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Histopathological Examination ◽

De Novo Lipogenesis ◽

Large Animal ◽

Alcoholic Fatty Liver ◽

High Fructose ◽

Alcoholic Fatty Liver Disease

AbstractNon-alcoholic fatty liver disease (NAFLD) is an increasingly prevalent condition that has been linked to high-fructose corn syrup consumption with induction of hepatic de novo lipogenesis (DNL) as the suggested central mechanism. Feeding diets very high in fructose (> 60%) rapidly induce several features of NAFLD in rodents, but similar diets have not yet been applied in larger animals, such as pigs. With the aim to develop a large animal NAFLD model, we analysed the effects of feeding a high-fructose (HF, 60% w/w) diet for four weeks to castrated male Danish Landrace-York-Duroc pigs. HF feeding upregulated expression of hepatic DNL proteins, but levels were low compared with adipose tissue. No steatosis or hepatocellular ballooning was seen on histopathological examination, and plasma levels of transaminases were similar between groups. Inflammatory infiltrates and the amount of connective tissue was slightly elevated in liver sections from fructose-fed pigs, which was corroborated by up-regulation of macrophage marker expression in liver homogenates. Supported by RNA-profiling, quantitative protein analysis, histopathological examination, and biochemistry, our data suggest that pigs, contrary to rodents and humans, are protected against fructose-induced steatosis by relying on adipose tissue rather than liver for DNL.

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A Narrative Review on the Role of AMPK on De Novo Lipogenesis in Non-Alcoholic Fatty Liver Disease: Evidence from Human Studies

Cells ◽

10.3390/cells10071822 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1822

Author(s):

Christian von Loeffelholz ◽

Sina M. Coldewey ◽

Andreas L. Birkenfeld

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Mammalian Cells ◽

De Novo ◽

Adenosine Monophosphate ◽

De Novo Lipogenesis ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver Disease

5′AMP-activated protein kinase (AMPK) is known as metabolic sensor in mammalian cells that becomes activated by an increasing adenosine monophosphate (AMP)/adenosine triphosphate (ATP) ratio. The heterotrimeric AMPK protein comprises three subunits, each of which has multiple phosphorylation sites, playing an important role in the regulation of essential molecular pathways. By phosphorylation of downstream proteins and modulation of gene transcription AMPK functions as a master switch of energy homeostasis in tissues with high metabolic turnover, such as the liver, skeletal muscle, and adipose tissue. Regulation of AMPK under conditions of chronic caloric oversupply emerged as substantial research target to get deeper insight into the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Evidence supporting the role of AMPK in NAFLD is mainly derived from preclinical cell culture and animal studies. Dysbalanced de novo lipogenesis has been identified as one of the key processes in NAFLD pathogenesis. Thus, the scope of this review is to provide an integrative overview of evidence, in particular from clinical studies and human samples, on the role of AMPK in the regulation of primarily de novo lipogenesis in human NAFLD.

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Metabolomic signatures of long-term coffee consumption and risk of type 2 diabetes in women

10.2337/figshare.12675611.v1 ◽

2020 ◽

Author(s):

Dong Hang ◽

Oana A. Zeleznik ◽

Xiaosheng He ◽

Marta Guasch-Ferre ◽

Xia Jiang ◽

...

Keyword(s):

Type 2 Diabetes ◽

Coffee Consumption ◽

Diabetes Risk ◽

Health Study ◽

Plasma Metabolites ◽

Case Control Studies ◽

Coffee Intake ◽

Decaffeinated Coffee ◽

Prediction Of Diabetes

Objective: Coffee may protect against multiple chronic diseases, particularly type 2 diabetes, but the mechanisms remain unclear. Research Design and Methods: Leveraging dietary and metabolomic data in two large cohorts of women (the Nurses’ Health Study I and II), we identified and validated plasma metabolites associated with coffee intake in 1595 women. We then evaluated the prospective association of coffee-related metabolites with diabetes risk and the added predictivity of these metabolites for diabetes in two nested case-control studies (n=457 cases and 1371 controls). Results: Of 461 metabolites, 34 were identified and validated to be associated with total coffee intake, including 13 positive associations (primarily trigonelline, polyphenol metabolites, and caffeine metabolites) and 21 inverse associations (primarily triacylglycerols and diacylglycerols). These associations were generally consistent for caffeinated and decaffeinated coffee, except for caffeine and its metabolites that were only associated with caffeinated coffee intake. The three cholesteryl esters positively associated with coffee intake showed inverse associations with diabetes risk, whereas the 12 metabolites negatively associated with coffee (five diacylglycerols and seven triacylglycerols) showed positive associations with diabetes. Adding the 15 diabetes-associated metabolites to classical risk factors-based prediction model increased the C-statistic from 0.79 (95% CI: 0.76, 0.83) to 0.83 (95% CI: 0.80, 0.86) (P<0.001). Similar improvement was observed in the validation set. Conclusion: Coffee consumption is associated with widespread metabolic changes, among which lipid metabolites may be critical for the anti- diabetes benefit of coffee. Coffee-related metabolites might help improve prediction of diabetes, but further validation studies <a>are </a>needed.

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Lupine (Lupinus angustifolius L.) Peptide Prevents Non-Alcoholic Fatty Liver Disease in High-Fat Diet-Induced Obese Mice

10.20944/preprints201907.0180.v1 ◽

2019 ◽

Author(s):

Ana Lemus-Conejo ◽

Elena Grao-Cruces ◽

Rocio Toscano ◽

Lourdes M Varela ◽

Carmen Claro ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

High Fat Diet ◽

Fatty Liver Disease ◽

Lupinus Angustifolius ◽

Standard Diet ◽

Obese Mice ◽

High Fat ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver Disease

Bioactive peptides are related to the prevention and treatment of many diseases. GPETAFLR is an octapeptide which was isolated from lupine (Lupinus angustifolius L.) and showed anti-inflammatory properties. The aim of this study was to evaluate the potential activity of GPETAFLR to prevent non-alcoholic fatty liver disease (NAFLD) in high-fat diet (HFD)-induced obese mice. C57BL/6J mice were fed a standard diet or an HFD. Two of the groups fed the HFD diet were treated with GPETAFLR in their drinking water at 0,5 mg/kg/d or 1 mg/kg/d. To determine the ability of GPETAFLR to improve the onset and progression of NAFLD, histological studies, hepatic enzyme profile, inflammatory cytokine and lipid metabolism-related genes and proteins were analyzed. Our results suggest that HFD-induced inflammatory metabolic disorders were alleviated by treatment with GPETAFLR. In conclusion, dietary lupine consumption could repair HFD-induced hepatic damage, possibly via modifications in the liver’s lipid signalling pathways.

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Adiponectin: A Key Adipokine in Alcoholic Fatty Liver

Experimental Biology and Medicine ◽

10.3181/0902-mr-61 ◽

2009 ◽

Vol 234 (8) ◽

pp. 850-859 ◽

Cited By ~ 74

Author(s):

Min You ◽

Christopher Q. Rogers

Keyword(s):

Fatty Liver ◽

De Novo ◽

Regulatory System ◽

Receptor Expression ◽

Sirtuin 1 ◽

De Novo Lipogenesis ◽

Lipid Lowering ◽

Acid Oxidation ◽

Alcoholic Fatty Liver ◽

Central Target

Alcoholic fatty liver is a major risk factor for advanced liver injuries such as steatohepatitis, fibrosis, and cirrhosis. While the underlying mechanisms are multiple, the development of alcoholic fatty liver has been attributed to a combined increase in the rate of de novo lipogenesis and a decrease in the rate of fatty acid oxidation in animal liver. Among various transcriptional regulators, the hepatic SIRT1 (sirtuin 1)-AMPK (AMPK-activated kinase) signaling system represents a central target for the action of ethanol in the liver. Adiponectin is one of the adipocyte-derived adipokines with potent lipid-lowering properties. Growing evidence has demonstrated that the development of alcoholic fatty liver is associated with reduced circulating adiponectin levels, decreased hepatic adiponectin receptor expression, and impaired hepatic adiponectin signaling. Adiponectin confers protection against alcoholic fatty liver via modulation of complex hepatic signaling pathways largely controlled by the central regulatory system, SIRT1-AMPK axis. This review aims to integrate the current research findings of ethanol-mediated dysregulation of adiponectin and its receptors and to provide a comprehensive point of view for understanding the role of adiponectin signaling in the development of alcoholic fatty liver.

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Leptin administration restores the altered adipose and hepatic expression of aquaglyceroporins improving the non-alcoholic fatty liver of ob/ob mice

Scientific Reports ◽

10.1038/srep12067 ◽

2015 ◽

Vol 5 (1) ◽

Cited By ~ 32

Author(s):

Amaia Rodríguez ◽

Natalia R. Moreno ◽

Inmaculada Balaguer ◽

Leire Méndez-Giménez ◽

Sara Becerril ◽

...

Keyword(s):

Fatty Liver ◽

Alcoholic Fatty Liver ◽

Hepatic Expression

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Treatment with Ginger Ameliorates Fructose-Induced Fatty Liver and Hypertriglyceridemia in Rats: Modulation of the Hepatic Carbohydrate Response Element-Binding Protein-Mediated Pathway

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2012/570948 ◽

2012 ◽

Vol 2012 ◽

pp. 1-12 ◽

Cited By ~ 27

Author(s):

Huanqing Gao ◽

Tao Guan ◽

Chunli Li ◽

Guowei Zuo ◽

Johji Yamahara ◽

...

Keyword(s):

Fatty Acid ◽

Fatty Liver ◽

Binding Protein ◽

Ppar Gamma ◽

De Novo Lipogenesis ◽

Nonesterified Fatty Acid ◽

Alcoholic Extract ◽

Response Element ◽

Hepatic Expression ◽

Element Binding Protein

Ginger has been demonstrated to improve lipid derangements. However, its underlying triglyceride-lowering mechanisms remain unclear. Fructose overconsumption is associated with increase in hepatic de novo lipogenesis, thereby resulting in lipid derangements. Here we found that coadministration of the alcoholic extract of ginger (50 mg/kg/day, oral gavage, once daily) over 5 weeks reversed liquid fructose-induced increase in plasma triglyceride and glucose concentrations and hepatic triglyceride content in rats. Plasma nonesterified fatty acid concentration was also decreased. Attenuation of the increased vacuolization and Oil Red O staining area was evident on histological examination of liver in ginger-treated rats. However, ginger treatment did not affect chow intake and body weight. Further, ginger treatment suppressed fructose-stimulated overexpression of carbohydrate response element-binding protein (ChREBP) at the mRNA and protein levels in the liver. Consequently, hepatic expression of the ChREBP-targeted lipogenic genes responsible for fatty acid biosynthesis was also downregulated. In contrast, expression of neither peroxisome proliferator-activated receptor- (PPAR-) alpha and its downstream genes, nor PPAR-gamma and sterol regulatory element-binding protein 1c was altered. Thus the present findings suggest that in rats, amelioration of fructose-induced fatty liver and hypertriglyceridemia by ginger treatment involves modulation of the hepatic ChREBP-mediated pathway.

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