Improved lipogenesis gene expression in liver is associated with elevated plasma angiotensin 1-7 after AT1 receptor blockade in insulin-resistant OLETF rats

Jose A. Godoy-Lugo*, Dora A. Mendez, Ruben Rodriguez, Akira Nishiyama, Daisuke Nakano, Jose G. Soñanez-Organis, Rudy M. Ortiz

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Increased angiotensin II (Ang II) signaling contributes to insulin resistance and liver steatosis. In addition to ameliorating hypertension, angiotensin receptor blockers (ARBs) improve lipid metabolism and hepatic steatosis, which are impaired with metabolic syndrome (MetS). Chronic blockade of the Ang II receptor type 1 (AT1) increases plasma angiotensin 1-7 (Ang 1–7), which mediates mechanisms counterregulatory to AT1 signaling. Elevated plasma Ang 1–7 is associated with decreased plasma triacylglycerol (TAG), cholesterol, glucose, and insulin; however, the benefits of RAS modulation to prevent non-alcoholic fatty liver disease (NAFLD) are not fully investigated. To better address the relationships among chronic ARB treatment, plasma Ang 1–7, and hepatic steatosis, three groups of 10-week-old-rats were studied: (1) untreated lean Long Evans Tokushima Otsuka (LETO), (2) untreated Otsuka Long Evans Tokushima Fatty (OLETF), and (3) OLETF + ARB (ARB; 10 mg olmesartan/kg/d × 6 weeks). Following overnight fasting, rats underwent an acute glucose load to better understand the dynamic metabolic responses during hepatic steatosis and early MetS. Tissues were collected at baseline (pre-load; T0) and 1 and 2 h post-glucose load. AT1 blockade increased plasma Ang 1–7 and decreased liver lipids, which was associated with decreased fatty acid transporter 5 (FATP5) and fatty acid synthase (FASN) expression. AT1 blockade decreased liver glucose and increased glucokinase (GCK) expression. These results demonstrate that during MetS, overactivation of AT1 promotes hepatic lipid deposition that is stimulated by an acute glucose load and lipogenesis genes, suggesting that the chronic hyperglycemia associated with MetS contributes to fatty liver pathologies via an AT1-mediated mechanism.

Original languageEnglish
Article number111729
JournalMolecular and Cellular Endocrinology
Volume555
DOIs
StatePublished - 15 Sep 2022

Bibliographical note

Funding Information:
Funding: Research was partially funded by University of California Mexico-United States (UC MEXUS) grant 19-194. JAGL was supported by the UC-MEXUS and the Consejo Nacional de Ciencia y Tecnologia (CONACYT) fellowship. JAGL and RR were supported by internal funding from University of California, Merced and by NIH NCMHD9T37MD001480.

Publisher Copyright:
© 2022

Keywords

  • ARB
  • Angiotensin receptor blocker
  • Glucokinase
  • Glycolysis
  • Non-alcoholic fatty liver disease

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