Losartan prevents hepatic steatosis and macrophage polarization by inhibiting hif-1α in a murine model of nafld

Cheng Hui Wang, Hsuan Miao Liu, Zi Yu Chang, Tse Hung Huang, Tzung Yan Lee*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

21 Scopus citations

Abstract

Hypoxia and hepatosteatosis microenvironments are fundamental traits of nonalcoholic fatty liver disease (NAFLD). Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that controls the cellular response to hypoxia and is activated in hepatocytes of patients with NAFLD, whereas the route and regulation of lipid droplets (LDs) and macrophage polarization related to systemic inflammation in NAFLD is unknown. Losartan is an angiotensin II receptor antagonist, that approved portal hypertension and related HIF-1α pathways in hepatic injury models. Here, we show that losartan in a murine model of NAFLD significantly decreased hepatic de novo lipogenesis (DNL) as well as suppressed lipid droplets (LDs), LD-associated proteins, perilipins (PLINs), and cell-death-inducing DNA-fragmentation-factor (DFF45)-like effector (CIDE) family in liver and epididymal white adipose tissues (EWAT) of ob/ob mice. Obesity-mediated macrophage M1 activation was also required for HIF-1α expression in the liver and EWAT of ob/ob mice. Administration of losartan significantly diminishes obesity-enhanced macrophage M1 activation and suppresses hepatosteatosis. Moreover, HIF-1α-mediated mitochondrial dysfunction was reversed in ob/ob mice treated with losartan. Together, the regulation of HIF-1α controls LDs protein expression and macrophage polarization, which highlights a potential target for losartan in NAFLD.

Original languageEnglish
Article number7841
JournalInternational Journal of Molecular Sciences
Volume22
Issue number15
DOIs
StatePublished - 01 08 2021

Bibliographical note

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • HIF-1α
  • Lipid droplet
  • Losartan
  • Macrophage polarization
  • Non-alcoholic fatty liver disease

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