scholarly journals Activation of mTORC1 by Free Fatty Acids Suppresses LAMP2 and Autophagy Function via ER Stress in Alcohol-Related Liver Disease

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2730
Author(s):  
Wei Guo ◽  
Wei Zhong ◽  
Liuyi Hao ◽  
Xinguo Sun ◽  
Zhanxiang Zhou
Keyword(s):  
Fatty Acids ◽  
Liver Disease ◽  
Liver Injury ◽  
Er Stress ◽  
Free Fatty Acids ◽  
Cell Injury ◽  
Autophagy Flux ◽  
Mtorc1 Signaling ◽  
Related Liver Disease ◽  
Mtorc1 Activation

Alcohol-related liver disease (ALD) is characterized by accumulation of hepatic free fatty acids (FFAs) and liver injury. The present study aimed to investigate if mechanistic target of rapamycin complex 1 (mTORC1) plays a role in FFA-induced organelle dysfunction, thereby contributing to the development of ALD. Cell studies were conducted to define the causal role and underlying mechanism of FFA-activated mTORC1 signaling in hepatocellular cell injury. C57BL/6J wild-type mice were subjected to chronic alcohol feeding with or without rapamycin to inhibit mTORC1 activation. We revealed that palmitic acid (PA)-induced ER stress and suppression of LAMP2 and autophagy flux were mTORC1-dependent as rapamycin reversed such deleterious effects. C/EBP homologous protein (CHOP) was downstream of ATF4 which partially modulated LAMP2. Supplementation with rapamycin to alcohol-fed mice attenuated mTORC1 activation and ER stress, restored LAMP2 protein, and improved autophagy, leading to amelioration of alcohol-induced liver injury. Induction of mTORC1 signaling and CHOP were also detected in the liver of patients with severe alcoholic hepatitis. This study demonstrates that hepatic FFAs play a crucial role in the pathogenesis of ALD by activating mTORC1 signaling, thereby inducing ER stress and suppressing LAMP2-autophagy flux pathway, which represents an important mechanism of FFA-induced hepatocellular injury.

scholarly journals Dynamin-related protein 1 deficiency accelerates lipopolysaccharide-induced acute liver injury and inflammation in mice

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Lixiang Wang ◽  
Xin Li ◽  
Yuki Hanada ◽  
Nao Hasuzawa ◽  
Yoshinori Moriyama ◽  
...  
Keyword(s):  
Liver Disease ◽  
Liver Injury ◽  
Er Stress ◽  
Disease Progression ◽  
Acute Liver Injury ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Mitochondrial Fusion ◽  
Related Protein ◽  
Liver Disease Progression

AbstractMitochondrial fusion and fission, which are strongly related to normal mitochondrial function, are referred to as mitochondrial dynamics. Mitochondrial fusion defects in the liver cause a non-alcoholic steatohepatitis-like phenotype and liver cancer. However, whether mitochondrial fission defect directly impair liver function and stimulate liver disease progression, too, is unclear. Dynamin-related protein 1 (DRP1) is a key factor controlling mitochondrial fission. We hypothesized that DRP1 defects are a causal factor directly involved in liver disease development and stimulate liver disease progression. Drp1 defects directly promoted endoplasmic reticulum (ER) stress, hepatocyte death, and subsequently induced infiltration of inflammatory macrophages. Drp1 deletion increased the expression of numerous genes involved in the immune response and DNA damage in Drp1LiKO mouse primary hepatocytes. We administered lipopolysaccharide (LPS) to liver-specific Drp1-knockout (Drp1LiKO) mice and observed an increased inflammatory cytokine expression in the liver and serum caused by exaggerated ER stress and enhanced inflammasome activation. This study indicates that Drp1 defect-induced mitochondrial dynamics dysfunction directly regulates the fate and function of hepatocytes and enhances LPS-induced acute liver injury in vivo.

Đường ngọt: thừa cân, béo phì và đái tháo đường

2019 ◽  
Author(s):  
Bá Thoại Trần
Keyword(s):  
Fatty Acids ◽  
Liver Disease ◽  
Fatty Liver ◽  
Free Fatty Acids ◽  
Nonalcoholic Fatty Liver Disease ◽  
Key Words ◽  
Fatty Liver Disease ◽  
Nonalcoholic Fatty Liver

Sugary carbohydrates in foods are sweet-tasted carbohydrates of mono or disacchride, most commonly is saccharose (sucrose). This is a disaccharide consisting of two molecules of glucose and fructose.While glucose is completely metabolized in all body cells to produce energy, fructose is metabolized differently in the liver causing nonalcoholic fatty liver disease and free fatty acids in the blood …. and causing many complications. Key words: Sugary carbohydrate, diabetes, overweight, obesity

Splanchnic Balance of Free Fatty Acids, Endocannabinoids, and Lipids in Subjects With Nonalcoholic Fatty Liver Disease

2010 ◽  
Vol 139 (6) ◽  
pp. 1961-1971.e1 ◽  
Author(s):  
Jukka Westerbacka ◽  
Anna Kotronen ◽  
Barbara A. Fielding ◽  
John Wahren ◽  
Leanne Hodson ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Liver Disease ◽  
Fatty Liver ◽  
Free Fatty Acids ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
Nonalcoholic Fatty Liver

Omega-3 Long Chain Polyunsaturated Fatty Acids for Treatment of Parenteral Nutrition–Associated Liver Disease: A Review of the Literature

2011 ◽  
Vol 16 (1) ◽  
pp. 31-38
Author(s):  
Emma M. Tillman ◽  
Richard A. Helms
Keyword(s):  
Fatty Acids ◽  
Liver Disease ◽  
Liver Injury ◽  
Parenteral Nutrition ◽  
Polyunsaturated Fatty Acids ◽  
Complex Disease ◽  
Omega 3 ◽  
The Past ◽  
Concurrent Use ◽  
Long Chain

ABSTRACT Parenteral nutrition–associated liver disease (PNALD) is a complex disease that is diagnosed by clinical presentation, biochemical markers of liver injury, concurrent use of parenteral nutrition (PN), and negative workup for other causes of liver disease. For the past 30 years, clinicians have had few effective treatments for PNALD and when disease progressed to liver cirrhosis it was historically associated with poor outcomes. Within the past 5 years there has been some encouraging evidence for the potential benefits of fish oils, rich in omega-3 long-chain polyunsaturated fatty acids (ω3PUFA), in reversing liver injury associated with PN. This article reviews the current literature relating to ω3PUFA and PNALD.

Alpha-1 antitrypsin governs alcohol-related liver disease in mice and humans

Gut ◽  
2020 ◽  
pp. gutjnl-2020-321375
Author(s):  
Christoph Grander ◽  
Benedikt Schaefer ◽  
Julian Schwärzler ◽  
Felix Grabherr ◽  
Dennis M de Graaf ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
Liver Disease ◽  
Liver Injury ◽  
Serum Concentration ◽  
Neutrophil Infiltration ◽  
Serum Concentrations ◽  
Cox Regression Analysis ◽  
Alpha 1 Antitrypsin ◽  
Related Liver Disease

ObjectiveAlcohol-related liver disease (ALD) is a global healthcare problem with limited treatment options. Alpha-1 antitrypsin (AAT, encoded by SERPINA1) shows potent anti-inflammatory activities in many preclinical and clinical trials. In our study, we aimed to explore the role of AAT in ALD.DesignAn unselected cohort of 512 patients with cirrhosis was clinically characterised. Survival, clinical and biochemical parameters including AAT serum concentration were compared between patients with ALD and other aetiologies of liver disease. The role of AAT was evaluated in experimental ALD models.ResultsCirrhotic ALD patients with AAT serum concentrations less than 120 mg/dL had a significantly higher risk for death/liver transplantation as compared with patients with AAT serum concentrations higher than 120 mg/dL. Multivariate Cox regression analysis showed that low AAT serum concentration was a NaMELD-independent predictor of survival/transplantation. Ethanol-fed wild-type (wt) mice displayed a significant decline in hepatic AAT compared with pair-fed mice. Therefore, hAAT-Tg mice were ethanol-fed, and these mice displayed protection from liver injury associated with decreased steatosis, hepatic neutrophil infiltration and abated expression of proinflammatory cytokines. To test the therapeutic capability of AAT, ethanol-fed wt mice were treated with human AAT. Administration of AAT ameliorated hepatic injury, neutrophil infiltration and steatosis.ConclusionCirrhotic ALD patients with AAT concentrations less than 120 mg/dL displayed an increased risk for death/liver transplantation. Both hAAT-Tg mice and AAT-treated wt animals showed protection from ethanol-induced liver injury. AAT could reflect a treatment option for human ALD, especially for alcoholic hepatitis.

scholarly journals The Protective Effect of Myristica fragrans Houtt. Extracts Against Obesity and Inflammation by Regulating Free Fatty Acids Metabolism in Nonalcoholic Fatty Liver Disease

Nutrients ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2507 ◽  
Author(s):  
Wenyu Zhao ◽  
Fanfen Song ◽  
Diangeng Hu ◽  
Haiqin Chen ◽  
Qixiao Zhai ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Liver Disease ◽  
Fatty Liver ◽  
Free Fatty Acids ◽  
High Fat Diet ◽  
Fatty Liver Disease ◽  
Lipid Synthesis ◽  
High Fat ◽  
Nonalcoholic Fatty Liver ◽  
Myristica Fragrans Houtt

Nonalcoholic fatty liver disease (NAFLD) is a disorder characterized by the excess accumulation of fat in the hepatocytes. It is commonly associated with severe obesity and inflammation. Free fatty acids (FFAs) are the key to regulate lipid metabolism and immune response in hepatocyte cells. This study examined the effects of AEN (alcohol extract of nutmeg, the seed of Myristica fragrans Houtt.) on the inhibition of lipid synthesis and inflammation in vitro and in vivo and on high-fat diet-induced obesity in NAFLD mice. Our results showed that AEN treatment could downregulate the expression of lipid synthesis-related genes fatty acid synthase (FASN) and sterol regulatory element-binding protein 1c (SREBP-1c) and lower the lipid content of cells. AEN also inhibited FFAs-mediated inflammation-related cytokines interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) expression in cells. In a mouse model, AEN reduced the bodyweight of obese mice and improved NAFLD without affecting food intake. Further analysis revealed that AEN significantly reduced inflammation level, cholesterol and lipid accumulation, blood glucose, and other liver function indexes in mice fed with a high-fat diet. In conclusion, AEN inhibited the aggravation of obesity and inflammation by downregulating lipid-gene expression in the liver to ameliorate NAFLD.

scholarly journals Saturated Fatty Acids Promote Endoplasmic Reticulum Stress and Liver Injury in Rats with Hepatic Steatosis

Endocrinology ◽  
2006 ◽  
Vol 147 (2) ◽  
pp. 943-951 ◽  
Author(s):  
Dong Wang ◽  
Yuren Wei ◽  
Michael J. Pagliassotti
Keyword(s):  
Fatty Acids ◽  
Endoplasmic Reticulum ◽  
Liver Disease ◽  
Liver Injury ◽  
Endoplasmic Reticulum Stress ◽  
Hepatic Steatosis ◽  
Fatty Liver Disease ◽  
Saturated Fatty Acids ◽  
Nonalcoholic Fatty Liver ◽  
Steatotic Liver

Nonalcoholic fatty liver disease is a relatively new hepatic sequela of obesity and type 2 diabetes. The pathogenesis of liver injury and disease progression in nonalcoholic fatty liver disease, however, is poorly understood. The present study examined the hypothesis that the composition of fatty acids in the steatotic liver promotes liver injury. Using dietary models of hepatic steatosis characterized by similar accumulation of total triglyceride but different composition of fatty acids, we show that hepatic steatosis characterized by increased saturated fatty acids is associated with increased liver injury and markers of endoplasmic reticulum stress (e.g. X-box binding protein-1 mRNA splicing and glucose-regulated protein 78 expression). These changes preceded and/or occurred independently of obesity and differences in leptin, TNFα, insulin action, and mitochondrial function. In addition, hepatic steatosis characterized by increased saturated fatty acids reduced proliferative capacity in response to partial hepatectomy and increased liver injury in response to lipopolysaccharide. These data suggest that the composition of fatty acids in the steatotic liver is an important determinant of susceptibility to liver injury.

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