Hypoxia‑inducible factor‑1α regulates Lipin1 differently in pre‑adipocytes and mature adipocytes

Kihira,Yoshitaka; Fujimura,Yoshino; Tomita,Shuhei; Tamaki,Toshiaki; Sato,Eiji

doi:10.3892/mmr.2020.11076

Hypoxia‑inducible factor‑1α regulates Lipin1 differently in pre‑adipocytes and mature adipocytes

Authors:
- Yoshitaka Kihira
- Yoshino Fujimura
- Shuhei Tomita
- Toshiaki Tamaki
- Eiji Sato
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Affiliations: Department of Clinical Pharmacy, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729‑0292, Japan, Department of Pharmacology, Osaka City University Graduate School of Medicine, Osaka‑shi 558‑8585, Japan, Department of Pharmacology, Institute of Biomedical Sciences, Tokushima University Graduate School, Kuramoto‑cho, Tokushima 770‑8503, Japan
Published online on: April 16, 2020 https://doi.org/10.3892/mmr.2020.11076
Pages: 559-565

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Abstract

Hypoxia-inducible factor (HIF)-1α is a transcription factor that is activated in low oxygen conditions. Adipose tissues are poorly oxygenated in patients with obesity. The low oxygen conditions in obese adipose tissues induce HIF‑1α in adipocytes. Previous studies using genetically modified mice suggest that HIF‑1α contributes to dysfunction in adipocytes. Lipin1 is a bifunctional protein that works as a phosphatidate phosphatase and transcriptional coactivator, which regulates lipid metabolism and adipogenesis, respectively. HIF‑1α directly regulates Lipin1 in hepatocytes. However, the regulation of Lipin1 by HIF‑1α in adipocytes is not well determined. Therefore, the present study investigated the regulation of Lipin1 by HIF‑1α in adipocytes. Expression levels of Lipin1 were reduced in epididymal adipose tissues of adipocyte‑specific HIF‑1α knockout mice, indicating that HIF‑1α regulates Lipin1 in adipocytes. In differentiated mature adipocytes, a HIF‑1α activator, dimethyloxallyl glycine (DMOG), was demonstrated to increase Lipin1, and a HIF‑1α inhibitor, 3‑(5'‑hydroxymethyl‑2'‑furyl)-1‑benzylindazole (YC‑1), reversed this increase, indicating that HIF‑1α regulates Lipin1 in differentiated adipocytes. However, during differentiation of pre‑adipocytes into adipocytes, YC‑1 increased Lipin1 even though HIF‑1α was decreased. The differentiation efficiency increased with YC‑1 treatment. In addition, DMOG reduced Lipin1 expression levels during differentiation despite increased HIF‑1α. Under these conditions, differentiation efficiency was reduced. These results suggest that Lipin1 is negatively regulated by HIF‑1α in pre‑adipocytes. Our results show that regulation of Lipin1 by HIF‑1α is different in adipocytes and pre‑adipocytes.

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