2. Academic Validation
  3. Hif1α/Dhrs3a Pathway Participates in Lipid Droplet Accumulation via Retinol and Ppar-γ in Fish Hepatocytes

Hif1α/Dhrs3a Pathway Participates in Lipid Droplet Accumulation via Retinol and Ppar-γ in Fish Hepatocytes

  • Int J Mol Sci. 2023 Jun 16;24(12):10236. doi: 10.3390/ijms241210236.
Jingjing Tian 1 2 3,  Yihui Du 1 2,  Binbin Wang 1 2,  Mengmeng Ji 1 2,  Hongyan Li 1 2 3,  Yun Xia 1 2 3,  Kai Zhang 1 2 3,  Zhifei Li 1 2 3,  Wenping Xie 1 2 3,  Wangbao Gong 1 2 3,  Ermeng Yu 1 2 3,  Guangjun Wang 1 2 3,  Jun Xie 1 2 3
Affiliations

Affiliations

  • 1 Key Laboratory of Aquatic Animal Immune Technology of Guangdong Province, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510380, China.
  • 2 Key Laboratory of Tropical and Subtropical Fishery Resource Application and Cultivation, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510380, China.
  • 3 Hainan Fisheries Innovation Research Institute, Chinese Academy of Fishery Sciences, Sanya 572024, China.
PMID: 37373386 DOI: 10.3390/ijms241210236
Abstract

Excessive hepatic lipid accumulation is a common phenomenon in cultured fish; however, its underlying mechanisms are poorly understood. Lipid droplet (LD)-related proteins play vital roles in LD accumulation. Herein, using a zebrafish liver cell line (ZFL), we show that LD accumulation is accompanied by differential expression of seven LD-annotated genes, among which the expression of dehydrogenase/reductase (SDR family) member 3 a/b (dhrs3a/b) increased synchronously. RNAi-mediated knockdown of dhrs3a delayed LD accumulation and downregulated the mRNA expression of Peroxisome Proliferator-activated Receptor gamma (pparg) in cells incubated with fatty acids. Notably, Dhrs3 catalyzed retinene to retinol, the content of which increased in LD-enriched cells. The addition of exogenous retinyl acetate maintained LD accumulation only in cells incubated in a lipid-rich medium. Correspondingly, exogenous retinyl acetate significantly increased pparg mRNA expression levels and altered the lipidome of the cells by increasing the phosphatidylcholine and triacylglycerol contents and decreasing the cardiolipin, phosphatidylinositol, and phosphatidylserine contents. Administration of LW6, an hypoxia-inducible factor 1α (HIF1α) inhibitor, reduced the size and number of LDs in ZFL cells and attenuated hif1αa, hif1αb, dhrs3a, and pparg mRNA expression levels. We propose that the HIF-1α/Dhrs3a pathway participates in LD accumulation in hepatocytes, which induces retinol formation and the Ppar-γ pathway.

Keywords

aquaculture; cell culture; fatty acid; fatty liver; hypoxia; lipid droplet; lipoprotein; liver; retinoids.

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