Signal transducer and activator of transcription 5 plays a crucial role in hepatic lipid metabolism through regulation of CD36 expression

Atsushi Hosui; Tomohide Tatsumi; Hayato Hikita; Yoshinobu Saito; Naoki Hiramatsu; Masahiko Tsujii; Lothar Hennighausen; Tetsuo Takehara

doi:10.1111/hepr.12816

Signal transducer and activator of transcription 5 plays a crucial role in hepatic lipid metabolism through regulation of CD36 expression

Hepatol Res. 2017 Jul;47(8):813-825. doi: 10.1111/hepr.12816. Epub 2016 Oct 18.

Authors

Atsushi Hosui^{1

2}, Tomohide Tatsumi¹, Hayato Hikita¹, Yoshinobu Saito¹, Naoki Hiramatsu^{1

2}, Masahiko Tsujii^{1

2}, Lothar Hennighausen³, Tetsuo Takehara¹

Affiliations

¹ Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.
² Division of Hepatobiliary and Pancreatic Diseases, Osaka-Rosai Hospital, Sakai, Japan.
³ Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.

PMID: 27593674
DOI: 10.1111/hepr.12816

Abstract

Aim: Liver-specific signal transducer and activator of transcription (STAT)5-deficient mice (STAT5KO) show lipid accumulation in the liver. We investigated the role of hepatic STAT5 in lipid metabolism in vitro and in vivo.

Methods and results: High expression of CD36, one of the receptors for free fatty acids, is associated with a high concentration of hepatic triglyceride (TG) in STAT5KO mice. Peroxisome proliferator-activated receptor (PPAR)γ, one of the regulatory factors of CD36, was upregulated and microRNA (miR)-20b was downregulated in STAT5KO mice. Reporter assays revealed direct regulation involving miR-20b and the 3'-untranslated region of CD36 mRNA. Treatment with free fatty acids enhanced accumulation of TG in STAT5-deleted hepatoma cells, and this was partially canceled by introduction of siRNA for PPARγ and/or pre-miR-20b through inhibition of CD36 expression. In vivo, STAT5/CD36 double knockout mice displayed hepatic TG was decreased compared to STAT5KO mice and it was also reduced by treatment with PPARγ antagonists, GW9662, and/or pre-miR-20b.

Conclusions: Signal transducer and activator of transcription 5 plays an important role in hepatic fat metabolism through regulation of CD36, and is a potential therapeutic candidate for liver steatosis.

Keywords: CD36; PPARγ; STAT5; fatty liver; triglyceride.