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http://dx.doi.org/10.5352/JLS.2021.31.9.796

SREBP-1c Ablation Protects Against ER Stress-induced Hepatic Steatosis by Preventing Impaired Fatty Acid Oxidation  

Lee, Young-Seung (Department of Animal Science, Chonnam National University)
Osborne, Timothy F. (Institute for Fundamental Biomedical Research, Department of Medicine and Biological Chemistry, Johns Hopkins University School of Medicine)
Seo, Young-Kyo (Aging Research Center, Korea Research Institute of Bioscience and Biotechnology)
Jeon, Tae-Il (Department of Animal Science, Chonnam National University)
Publication Information
Journal of Life Science / v.31, no.9, 2021 , pp. 796-805 More about this Journal
Abstract
Hepatic endoplasmic reticulum (ER) stress contributes to the development of steatosis and insulin resistance. The components of unfolded protein response (UPR) regulate lipid metabolism. Recent studies have reported an association between ER stress and aberrant cellular lipid control; moreover, research has confirmed the involvement of sterol regulatory element-binding proteins (SREBPs)-the central regulators of lipid metabolism-in the process. However, the exact role of SREBPs in controlling lipid metabolism during ER stress and its contribution to fatty liver disease remain unknown. Here, we show that SREBP-1c deficiency protects against ER stress-induced hepatic steatosis in mice by regulating UPR, inflammation, and fatty acid oxidation. SREBP-1c directly regulated inositol-requiring kinase 1α (IRE1α) expression and mediated ER stress-induced tumor necrosis factor-α activation, leading to a reduction in expression of peroxisome proliferator-activated receptor γ coactivator 1-α and subsequent impairment of fatty acid oxidation. However, the genetic ablation of SREBP-1c prevented these events, alleviating hepatic inflammation and steatosis. Although the mechanism by which SREBP-1c deficiency prevents ER stress-induced inflammatory signaling remains to be elucidated, alteration of the IRE1α signal in SREBP-1c-depleted Kupffer cells might be involved in the signaling. Overall, the results suggest that SREBP-1c plays a crucial role in the regulation of UPR and inflammation in ER stress-induced hepatic steatosis.
Keywords
ER stress; fatty acid oxidation; hepatic steatosis; SREBP-1c; unfolded protein response;
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