Angiotensinogen in hepatocytes contributes to Western diet-induced liver steatosis.

Abstract

Nonalcoholic fatty liver disease (NAFLD) is considered as a liver manifestation of metabolic disorders. Previous studies indicate that the renin-angiotensin system (RAS) plays a complex role in NAFLD. As the only precursor of the RAS, decreased angiotensinogen (AGT) profoundly impacts RAS bioactivity. Here, we investigated the role of hepatocyte-derived AGT in liver steatosis. AGT floxed mice (hepAGT+/+) and hepatocyte-specific AGT-deficient mice (hepAGT-/-) were fed a Western diet and a normal laboratory diet for 12 weeks, respectively. Compared with hepAGT+/+ mice, Western diet-fed hepAGT-/- mice gained less body weight with improved insulin sensitivity. The attenuated severity of liver steatosis in hepAGT-/- mice was evidenced by histologic changes and reduced intrahepatic triglycerides. The abundance of SREBP1 and its downstream molecules, acetyl-CoA carboxylase and FASN, was suppressed in hepAGT-/- mice. Furthermore, serum derived from hepAGT+/+ mice stimulated hepatocyte SREBP1 expression, which could be diminished by protein kinase B (Akt)/mammalian target of rapamycin (mTOR) inhibition in vitro. Administration of losartan did not affect diet-induced body weight gain, liver steatosis severity, and hepatic p-Akt, p-mTOR, and SREBP1 protein abundance in hepAGT+/+ mice. These data suggest that attenuation of Western diet-induced liver steatosis in hepAGT-/- mice is associated with the alternation of the Akt/mTOR/SREBP-1c pathway.

• Authors: Xin-Ran Tao, Jia-Bing Rong, Hong S Lu, Alan Daugherty, Peng Shi, Chang-Le Ke, Zhao-Cai Zhang, Yin-Chuan Xu, Jian-An Wang
• Journal: Journal of lipid research (J Lipid Res) Vol. 60 Issue 12 Pg. 1983-1995 (12 2019) ISSN: 1539-7262 [Electronic] United States
• PMID: 31604805 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Tao et al. Published by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Fatty Acids
• Sterol Regulatory Element Binding Protein 1
• Angiotensinogen
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases

Topics

• Angiotensinogen (deficiency, metabolism)
• Animals
• Diet, Western (adverse effects)
• Fatty Acids (metabolism)
• Hepatocytes (drug effects, metabolism)
• Mice
• Non-alcoholic Fatty Liver Disease (chemically induced, metabolism, pathology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Renin-Angiotensin System (drug effects)
• Signal Transduction (drug effects)
• Sterol Regulatory Element Binding Protein 1 (metabolism)
• TOR Serine-Threonine Kinases (metabolism)