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PCSK9 REDUCES HEPATIC LIPID CONTENT AND CONFERS PROTECTION AGAINST ER STRESS AND ROS IN HEPG2 CELLS
Author(s) -
Byun Jae Hyun,
Lebeau Paul,
AlHashimi Ali,
Platko Khrystyna C.,
Trigatti Bernardo,
Seidah Nabil G.,
Austin Richard C.
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.539.8
Subject(s) - lipotoxicity , pcsk9 , unfolded protein response , endocrinology , medicine , ldl receptor , steatosis , palmitic acid , steatohepatitis , chemistry , fatty liver , biology , fatty acid , endoplasmic reticulum , lipoprotein , cholesterol , biochemistry , insulin resistance , disease , diabetes mellitus
Characterized by excess hepatic lipid accumulation, hepatic steatosis frequently leads to hepatocyte injury and onset of nonalcoholic steatohepatitis (NASH). Recently, the discovery of a bona fide regulator of the low‐density lipoprotein (LDL) receptor (LDLR), the proprotein convertase subtilisin/kexin type‐9 (PCSK9), has lead to the development of novel therapeutics that reduce circulating LDL levels by 60% in patients at high risk of developing cardiovascular disease (CVD). By blocking PCSK9‐mediated LDLR degradation, however, PCSK9 inhibitors can increase liver burden by promoting hepatic lipid uptake. Although the success of PCSK9 inhibitors in reducing circulating LDL levels is unparalleled, we have observed hepatic lipid accumulation in a variety of PCSK9 knockout models. In cultured hepatocytes, PCSK9 protects from palmitic acid‐induced lipid droplet formation, endoplasmic reticulum (ER) stress, reactive oxygen species production and cell death. In contrast to our in vitro findings, the livers of PCSK9 KO mice exhibit excess lipid content, but show no sign of ER stress or cell death. The effect of saturated fatty acids, like palmitic acid, or high‐fat‐diet on the induction of hepatic ER stress and lipotoxicity in PCSK9 KO mice remains to be elucidated. Support or Funding Information This work was supported in part by research grants to Richard C. Austin from the Heart and Stroke Foundation of Ontario (T‐6146), the Heart and Stroke Foundation of Canada (G‐13‐0003064 and G‐15‐0009389) and the Canadian Institutes of Health Research (74477).Schematic diagram of PCSK9 and its role in regulating hepatic receptorsThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .