scholarly journals Hepatic HuR protects against the pathogenesis of non-alcoholic fatty liver disease

2020 ◽  
Author(s):  
Mi Tian ◽  
Xinyun Li ◽  
Jingyuan Li ◽  
Jianmin Yang ◽  
Cheng Zhang ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Hepatic Steatosis ◽  
High Fat Diet ◽  
Chow Diet ◽  
Alcoholic Fatty Liver ◽  
Over Expression ◽  
Regulator Protein ◽  
Normal Chow ◽  
Alcoholic Fatty Liver Disease

Abstract Background: Liver plays an important role in lipid and glucose metabolism. Human antigen R (HuR) as an RNA regulator protein participates in many disease processes. Here, we investigated the specific role of HuR in hepatic steatosis and glucose metabolism.Methods: We investigated the level of HuR in liver from mice fed a normal chow diet (NCD) and high fat diet (HFD). Liver specific HuR knockout (HuRLKO) mice were generated and challenged with an HFD. Lipid levels and glucose metabolism index were examined. Results: HuR was downregulated in livers of HFD-fed mice. HuRLKO mice showed exacerbated HFD-induced hepatic steatosis but improved glucose tolerance as compared with controls. Consistently, HuR inhibited lipid accumulation in hepatocytes. Mechanically, HuR could bind to the mRNA of phosphatase and tensin homology deleted on chromosome 10 (PTEN), thus increasing their stability and translation. Finally, PTEN over-expression alleviated HFD-induced hepatic steatosis in HuRLKO mice.Conclusion: HuR modulates lipid and glucose metabolism through regulating PTEN expression.

scholarly journals Hepatic HuR protects against the pathogenesis of non-alcoholic fatty liver disease by targeting PTEN

2021 ◽  
Vol 12 (3) ◽  
Author(s):  
Mi Tian ◽  
Jingjing Wang ◽  
Shangming Liu ◽  
Xinyun Li ◽  
Jingyuan Li ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Hepatic Steatosis ◽  
Chow Diet ◽  
Alcoholic Fatty Liver ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Pten Mrna ◽  
Normal Chow ◽  
Mice Liver

AbstractThe liver plays an important role in lipid and glucose metabolism. Here, we show the role of human antigen R (HuR), an RNA regulator protein, in hepatocyte steatosis and glucose metabolism. We investigated the level of HuR in the liver of mice fed a normal chow diet (NCD) and a high-fat diet (HFD). HuR was downregulated in the livers of HFD-fed mice. Liver-specific HuR knockout (HuRLKO) mice showed exacerbated HFD-induced hepatic steatosis along with enhanced glucose tolerance as compared with control mice. Mechanistically, HuR could bind to the adenylate uridylate-rich elements of phosphatase and tensin homolog deleted on the chromosome 10 (PTEN) mRNA 3′ untranslated region, resulting in the increased stability of Pten mRNA; genetic knockdown of HuR decreased the expression of PTEN. Finally, lentiviral overexpression of PTEN alleviated the development of hepatic steatosis in HuRLKO mice in vivo. Overall, HuR regulates lipid and glucose metabolism by targeting PTEN.

scholarly journals Effects of a Low Dose of Caffeine Alone or as Part of a Green Coffee Extract, in a Rat Dietary Model of Lean Non-Alcoholic Fatty Liver Disease without Inflammation

Nutrients ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3240
Author(s):  
Ana Magdalena Velázquez ◽  
Núria Roglans ◽  
Roger Bentanachs ◽  
Maria Gené ◽  
Aleix Sala-Vila ◽  
...  
Keyword(s):  
Liver Disease ◽  
Hepatic Steatosis ◽  
High Fat Diet ◽  
Fatty Liver Disease ◽  
Low Dose ◽  
Female Rats ◽  
Green Coffee ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease is a highly prevalent condition without specific pharmacological treatment, characterized in the initial stages by hepatic steatosis. It was suggested that lipid infiltration in the liver might be reduced by caffeine through anti-inflammatory, antioxidative, and fatty acid metabolism-related mechanisms. We investigated the effects of caffeine (CAF) and green coffee extract (GCE) on hepatic lipids in lean female rats with steatosis. For three months, female Sprague-Dawley rats were fed a standard diet or a cocoa butter-based high-fat diet plus 10% liquid fructose. In the last month, the high-fat diet was supplemented or not with CAF or a GCE, providing 5 mg/kg of CAF. Plasma lipid levels and the hepatic expression of molecules involved in lipid metabolism were determined. Lipidomic analysis was performed in liver samples. The diet caused hepatic steatosis without obesity, inflammation, endoplasmic reticulum stress, or hepatic insulin resistance. Neither CAF nor GCE alleviated hepatic steatosis, but GCE-treated rats showed lower hepatic triglyceride levels compared to the CAF group. The GCE effects could be related to reductions of hepatic (i) mTOR phosphorylation, leading to higher nuclear lipin-1 levels and limiting lipogenic gene expression; (ii) diacylglycerol levels; (iii) hexosylceramide/ceramide ratios; and (iv) very-low-density lipoprotein receptor expression. In conclusion, a low dose of CAF did not reduce hepatic steatosis in lean female rats, but the same dose provided as a green coffee extract led to lower liver triglyceride levels.

scholarly journals Prebiotic Xylo-Oligosaccharides Ameliorate High-Fat-Diet-Induced Hepatic Steatosis in Rats

Nutrients ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3225
Author(s):  
Sanna Lensu ◽  
Raghunath Pariyani ◽  
Elina Mäkinen ◽  
Baoru Yang ◽  
Wisam Saleem ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
High Fat Diet ◽  
Alcoholic Fatty Liver ◽  
Branched Chain Fatty Acids ◽  
Hepatic Fat ◽  
Branched Chain ◽  
Underlying Mechanisms ◽  
A Minor ◽  
Alcoholic Fatty Liver Disease

Understanding the importance of the gut microbiota (GM) in non-alcoholic fatty liver disease (NAFLD) has raised the hope for therapeutic microbes. We have shown that high hepatic fat content associated with low abundance of Faecalibacterium prausnitzii in humans and, further, the administration of F. prausnitzii prevented NAFLD in mice. Here, we aimed at targeting F. prausnitzii by prebiotic xylo-oligosaccharides (XOS) to treat NAFLD. First, the effect of XOS on F. prausnitzii growth was assessed in vitro. Then, XOS was supplemented or not with high (HFD, 60% of energy from fat) or low (LFD) fat diet for 12 weeks in Wistar rats (n = 10/group). XOS increased F. prausnitzii growth, having only a minor impact on the GM composition. When supplemented with HFD, XOS ameliorated hepatic steatosis. The underlying mechanisms involved enhanced hepatic β-oxidation and mitochondrial respiration. Nuclear magnetic resonance (1H-NMR) analysis of cecal metabolites showed that, compared to the HFD, the LFD group had a healthier cecal short-chain fatty acid profile and on the HFD, XOS reduced cecal isovalerate and tyrosine, metabolites previously linked to NAFLD. Cecal branched-chain fatty acids associated positively and butyrate negatively with hepatic triglycerides. In conclusion, XOS supplementation can ameliorate NAFLD by improving hepatic oxidative metabolism and affecting GM.

Hepatic accumulation of S-adenosylmethionine in hamsters with non-alcoholic fatty liver disease associated with metabolic syndrome under selenium and vitamin E deficiency

2019 ◽  
Vol 133 (3) ◽  
pp. 409-423 ◽  
Author(s):  
Josep Maria del Bas ◽  
Benjamín Rodríguez ◽  
Francesc Puiggròs ◽  
Silvia Mariné ◽  
Miguel Angel Rodríguez ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Metabolic Syndrome ◽  
Vitamin E ◽  
High Fat Diet ◽  
Fatty Liver Disease ◽  
Cell Cycle Control ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

AbstractProgression of non-alcoholic fatty liver disease (NAFLD) in the context of metabolic syndrome (MetS) is only partially explored due to the lack of preclinical models. In order to study the alterations in hepatic metabolism that accompany this condition, we developed a model of MetS accompanied by the onset of steatohepatitis (NASH) by challenging golden hamsters with a high-fat diet low in vitamin E and selenium (HFD), since combined deficiency results in hepatic necroinflammation in rodents. Metabolomics and transcriptomics integrated analyses of livers revealed an unexpected accumulation of hepatic S-Adenosylmethionine (SAM) when compared with healthy livers likely due to diminished methylation reactions and repression of GNMT. SAM plays a key role in the maintenance of cellular homeostasis and cell cycle control. In agreement, analysis of over-represented transcription factors revealed a central role of c-myc and c-Jun pathways accompanied by negative correlations between SAM concentration, MYC expression and AMPK phosphorylation. These findings point to a drift of cell cycle control toward senescence in livers of HFD animals, which could explain the onset of NASH in this model. In contrast, hamsters with NAFLD induced by a conventional high-fat diet did not show SAM accumulation, suggesting a key role of selenium and vitamin E in SAM homeostasis. In conclusion, our results suggest that progression of NAFLD in the context of MetS can take place even in a situation of hepatic SAM excess and that selenium and vitamin E status might be considered in current therapies against NASH based on SAM supplementation.

scholarly journals Role of Mcpip1 in obesity-induced hepatic steatosis as determined by myeloid and liver-specific conditional knockouts

2020 ◽  
Author(s):  
Natalia Pydyn ◽  
Dariusz Żurawek ◽  
Joanna Kozieł ◽  
Edyta Kuś ◽  
Kamila Wojnar-Lason ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Hepatic Steatosis ◽  
Systemic Inflammation ◽  
Hepatic Metabolism ◽  
Negative Regulator ◽  
Chow Diet ◽  
Alcoholic Fatty Liver ◽  
Hepatic Expression ◽  
Expression Of Genes ◽  
Myeloid Leukocytes

AbstractMonocyte chemoattractant protein-induced protein 1 (MCPIP1, alias Regnase1) is a negative regulator of inflammation, acting through cleavage of transcripts coding for proinflammatory cytokines and by inhibition of NFκB activity. Moreover, it was demonstrated, that MCPIP1 regulates lipid metabolism both in adipose tissue and hepatocytes. In this study, we investigated the effects of tissue-specific Mcpip1 deletion on the regulation of hepatic metabolism and development of non-alcoholic fatty liver disease (NAFLD).We used knock-in control Mcpip1fl/fl mice and animals with deletion of Mcpip1 in myeloid leukocytes (Mcpip1fl/flLysMCre) and in hepatocytes (Mcpip1fl/flAlbCre), which were fed chow or a high-fat diet (HFD) for 12 weeks. Mcpip1fl/flLysMCre mice were fed a chow diet were characterized by a significantly reduced hepatic expression of genes regulating lipid and glucose metabolism, which subsequently resulted in hypoglycemia and dyslipidemia. These animals also displayed systemic inflammation, demonstrated by increased concentrations of cytokines in the plasma. On the other hand, there were no significant changes in phenotype in Mcpip1fl/flAlbCre mice. Although we detected a reduced hepatic expression of genes regulating glucose metabolism and β-oxidation in these mice, they remained asymptomatic. Upon feeding them a HFD, Mcpip1fl/flLysMCre mice did not develop obesity, glucose intolerance, nor hepatic steatosis, but were characterized by hypoglycemia and dyslipidemia, along with proinflammatory phenotype with symptoms of cachexia. Mcpip1fl/flAlbCre animals, following a HFD, became hypercholesterolemic, but accumulated lipids in the liver at the same level as Mcpip1fl/fl mice, and no changes in the level of soluble factors tested in the plasma were detected.In conclusion, we have demonstrated that Mcpip1 protein plays an important role in the liver homeostasis. Depletion of Mcpip1 in myeloid leukocytes, followed by systemic inflammation, has a more pronounced effect on controlling liver metabolism and homeostasis than the depletion of Mcpip1 in hepatocytes.

Chronic high fat feeding and prolonged fasting in liver-specific ANGPTL4 knockout mice

2021 ◽  
Author(s):  
Kathryn Mary Spitler ◽  
Shwetha K Shetty ◽  
Emily M Cushing ◽  
Kelli L. Sylvers-Davie ◽  
Brandon S.J. Davies
Keyword(s):  
Glucose Tolerance ◽  
Glucose Intolerance ◽  
High Fat Diet ◽  
Plasma Triglyceride ◽  
Chow Diet ◽  
Loss Of Function ◽  
High Fat ◽  
Prolonged Fasting ◽  
Normal Chow

Obesity is associated with dyslipidemia, ectopic lipid deposition and insulin resistance. In mice, the global or adipose-specific loss of function of the protein angiopoietin-like 4 (ANGPTL4) leads to decreased plasma triglyceride levels, enhanced adipose triglyceride uptake, and protection from high-fat diet-induced glucose intolerance. ANGPTL4 is also expressed highly in the liver, but the role of liver-derived ANGPTL4 is unclear. The goal of this study was to determine the contribution of hepatocyte ANGPTL4 to triglyceride and glucose homeostasis in mice during a high fat diet challenge. We generated hepatocyte-specific ANGPTL4 deficient (Angptl4LivKO) mice, fed them a 60% kCal/fat diet (HFD) for 6 months, and assessed triglyceride, liver, and glucose metabolic phenotypes. We also explored the effects of prolonged fasting on Angptl4LivKO mice. The loss of hepatocyte-derived Angptl4 led to no major changes in triglyceride partitioning or lipoprotein lipase activity compared to control mice. Interestingly, although there was no difference in fasting plasma triglyceride levels after a 6 h fast, after an 18 h fast normal chow diet fed Angptl4LivKO mice had lower triglyceride levels than control mice. On a HFD, Angptl4LivKO mice initially showed no difference in glucose tolerance and insulin sensitivity, but improved glucose tolerance emerged in these mice after 6 months on HFD. Our data suggest that hepatocyte ANGPTL4 does not directly regulate triglyceride partitioning, but that loss of liver-derived ANGPTL4 may be protective from HFD-induced glucose intolerance and influence plasma TG metabolism during prolonged fasting.

scholarly journals SREBP-2/PNPLA8 axis improves non-alcoholic fatty liver disease through activation of autophagy

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Kwang-Youn Kim ◽  
Hyun-Jun Jang ◽  
Yong Ryoul Yang ◽  
Kwang-Il Park ◽  
JeongKon Seo ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
High Fat Diet ◽  
Fatty Liver Disease ◽  
Hepatic Triglyceride ◽  
Alcoholic Fatty Liver ◽  
Over Expression ◽  
Beneficial Effects ◽  
Triglyceride Accumulation ◽  
Alcoholic Fatty Liver Disease

Abstract Dysregulated autophagy is associated with steatosis and non-alcoholic fatty liver disease (NAFLD), however the mechanisms connecting them remain poorly understand. Here, we show that co-administration of lovastatin and ezetimibe (L/E) significantly reverses hepatic triglyceride accumulation concomitant with an increase in SREBP-2 driven autophagy in mice fed a high-fat diet (HFD). We further show that the statin mediated increase in SREBP-2 directly activates expression of patatin-like phospholipase domain-containing enzyme 8 (PNPLA8) gene, and PNPLA8 associates with autophagosomes and is associated with a decrease in cellular triglyceride. Moreover, we show that over-expression of PNPLA8 dramatically decreases hepatic steatosis through increased autophagy in hepatocytes of HFD-fed mice. Live-cell imaging analyses also reveal that PNPLA8 dynamically interacts with LC3 and we suggest that the SREBP-2/PNPLA8 axis represents a novel regulatory mechanism for lipid homeostasis. These data provide a possible mechanism for the reported beneficial effects of statins for decreasing hepatic triglyceride levels in NAFLD patients.

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