Nonalcoholic Fatty Liver
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2021 ◽  
Vol 385 (17) ◽  
pp. 1559-1569 ◽  
Author(s):  
Arun J. Sanyal ◽  
Mark L. Van Natta ◽  
Jeanne Clark ◽  
Brent A. Neuschwander-Tetri ◽  
AnnaMae Diehl ◽  
...  

2021 ◽  
Author(s):  
Wei Liu ◽  
Chao Sun ◽  
Ying Yan ◽  
Hongchao Cao ◽  
Zhoumin Niu ◽  
...  

The mechanisms underlying the pathogenesis of steatosis and insulin resistance in nonalcoholic fatty liver disease remain elusive. Increased phosphorylation of hepatic p38 has long been noticed in fatty liver; however, whether the activation of hepatic p38 is a cause or consequence of liver steatosis is unclear. Here, we demonstrate that hepatic p38 activation by MKK6 overexpression in the liver of mice induces severe liver steatosis, reduces fat mass, and elevates circulating fatty acid levels in a hepatic p38a- and FGF21-dependent manner. Mechanistically, through increasing the FGF21 production from liver, hepatic p38 activation increases the influx of fatty acids from adipose tissue to liver, leading to hepatic ectopic lipid accumulation and insulin resistance. Although hepatic p38 activation exhibits favorable effects in peripheral tissues, it impairs the hepatic FGF21 action by facilitating the ubiquitination and degradation of FGF21 receptor cofactor b-Klotho. Consistently, we show that p38 phosphorylation and FGF21 expression are increased, b-Klotho protein levels are decreased in the fatty liver of either mice or patients. In conclusion, our study reveals previously undescribed effects of hepatic p38 activation on systemic metabolism and provides new insights into the roles of hepatic p38a, FGF21, and b-Klotho in the pathogenesis of nonalcoholic fatty liver disease.


2021 ◽  
Author(s):  
Wei Liu ◽  
Chao Sun ◽  
Ying Yan ◽  
Hongchao Cao ◽  
Zhoumin Niu ◽  
...  

The mechanisms underlying the pathogenesis of steatosis and insulin resistance in nonalcoholic fatty liver disease remain elusive. Increased phosphorylation of hepatic p38 has long been noticed in fatty liver; however, whether the activation of hepatic p38 is a cause or consequence of liver steatosis is unclear. Here, we demonstrate that hepatic p38 activation by MKK6 overexpression in the liver of mice induces severe liver steatosis, reduces fat mass, and elevates circulating fatty acid levels in a hepatic p38a- and FGF21-dependent manner. Mechanistically, through increasing the FGF21 production from liver, hepatic p38 activation increases the influx of fatty acids from adipose tissue to liver, leading to hepatic ectopic lipid accumulation and insulin resistance. Although hepatic p38 activation exhibits favorable effects in peripheral tissues, it impairs the hepatic FGF21 action by facilitating the ubiquitination and degradation of FGF21 receptor cofactor b-Klotho. Consistently, we show that p38 phosphorylation and FGF21 expression are increased, b-Klotho protein levels are decreased in the fatty liver of either mice or patients. In conclusion, our study reveals previously undescribed effects of hepatic p38 activation on systemic metabolism and provides new insights into the roles of hepatic p38a, FGF21, and b-Klotho in the pathogenesis of nonalcoholic fatty liver disease.


Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 2806
Author(s):  
Rui Xue ◽  
Lianyong Su ◽  
Shengyi Lai ◽  
Yanyan Wang ◽  
Derrick Zhao ◽  
...  

The prevalence of nonalcoholic fatty liver disease (NAFLD) has been significantly increased due to the global epidemic of obesity. The disease progression from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH) is closely linked to inflammation, insulin resistance, and dysbiosis. Although extensive efforts have been aimed at elucidating the pathological mechanisms of NAFLD disease progression, current understanding remains incomplete, and no effective therapy is available. Bile acids (BAs) are not only important physiological detergents for the absorption of lipid-soluble nutrients in the intestine but also metabolic regulators. During the last two decades, BAs have been identified as important signaling molecules involved in lipid, glucose, and energy metabolism. Dysregulation of BA homeostasis has been associated with NAFLD disease severity. Identification of nuclear receptors and G-protein-coupled receptors activated by different BAs not only significantly expanded the current understanding of NAFLD/NASH disease progression but also provided the opportunity to develop potential therapeutics for NAFLD/NASH. In this review, we will summarize the recent studies with a focus on BA-mediated signaling pathways in NAFLD/NASH. Furthermore, the therapeutic implications of targeting BA-mediated signaling pathways for NAFLD will also be discussed.


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