Chronic angiotensin receptor activation promotes hepatic triacylglycerol accumulation during an acute glucose challenge in obese-insulin-resistant OLETF rats

Jose A. Godoy-Lugo*, Max A. Thorwald, David Y. Hui, Akira Nishiyama, Daisuke Nakano, Jose G. Soñanez-Organis, Rudy M. Ortiz

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Angiotensin receptor blockers (ARBs) can ameliorate metabolic syndrome (MetS)-associated dyslipidemia, hepatic steatosis, and glucose intolerance, suggesting that angiotensin receptor (AT1) over-activation contributes to impaired lipid and glucose metabolism, which is characteristic of MetS. The aim of this study was to evaluate changes in the lipid profile and proteins of fatty acid uptake, triacylglycerol (TAG) synthesis, and β-oxidation to better understand the links between AT1 overactivation and non-alcoholic fatty liver disease (NAFLD) during MetS. Methods: Four groups of 25-week-old-rats were used: (1) untreated LETO, (2) untreated OLETF, (3) OLETF + angiotensin receptor blocker (ARB; 10 mg olmesartan/kg/d × 8 weeks) and (4) OLETF ± ARB (MINUS; 10 mg olmesartan/kg/d × 4 weeks, then removed until dissection). To investigate the dynamic shifts in metabolism, animals were dissected after an oral glucose challenge (fasting, 3 and 6 h post-glucose). Results: Compared to OLETF, plasma total cholesterol and TAG remained unchanged in ARB. However, liver TAG was 55% lesser in ARB than OLETF, and remained lower throughout the challenge. Basal CD36 and ApoB were 28% and 29% lesser, respectively, in ARB than OLETF. PRDX6 abundance in ARB was 45% lesser than OLETF, and it negatively correlated with liver TAG in ARB. Conclusions: Chronic blockade of AT1 protects the liver from TAG accumulation during glucose overload. This may be achieved by modulating NEFA uptake and increasing TAG export via ApoB. Our study highlights the contributions of AT1 signaling to impaired hepatic substrate metabolism and the detriments of a high-glucose load and its potential contribution to steatosis during MetS.

Original languageEnglish
Pages (from-to)92-107
Number of pages16
JournalEndocrine
Volume75
Issue number1
DOIs
StatePublished - Jan 2022

Bibliographical note

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

Publisher Copyright:
© 2021, The Author(s).

Keywords

  • ARB, Insulin resistance
  • Angiotensin receptor blocker
  • Liver steatosis
  • Metabolic syndrome
  • NAFLD

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