Angiotensinogen in hepatocytes contributes to Western diet-induced liver steatosis

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

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10 Scopus citations

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 hep- AGT+/+ 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 dietinduced liver steatosis in hepAGT-/- mice is associated with the alternation of the Akt/mTOR/SREBP-1c pathway.

Original languageEnglish
Pages (from-to)1983-1995
Number of pages13
JournalJournal of Lipid Research
Volume60
Issue number12
DOIs
StatePublished - 2019

Bibliographical note

Funding Information:
This work was supported by National Natural Science Foundation of China Grants 81870292 (J-A.W.), 81971860 (Y-C.X.), 81500876 (Y-C.X.), and 81772110 (Z-C.Z); National Key Research and Development Program of China Grant 2016YFC1301204 (J-A.W.); and Natural Science Foundation of Zheji-ang Province Grant LQ16H020003 (Y-C.X.). Author’s Choice—Final version open access under the terms of the Creative Commons CC-BY license. Manuscript received 13 February 2019 and in revised form 9 October 2019. Published, JLR Papers in Press, October 11, 2019 DOI https://doi.org/10.1194/jlr.M093252

Publisher Copyright:
© 2019 Tao et al.

Keywords

  • Diet and diet lipids
  • Fatty acid/biosynthesis
  • Lipolysis and fatty acid metabolism
  • Nonalcoholic fatty liver disease
  • Nuclear receptor/Srebp
  • Triglycerides

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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