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Development of Nonalcoholic Fatty Liver in Superoxide Dismutase‐1 Knockout Mice Was Associated with Altered Expression of Hepatic Fibroblast Growth Factor‐21
Author(s) -
Chakraborty Debrup,
Lei Xin Gen
Publication year - 2016
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.30.1_supplement.267.7
Subject(s) - knockout mouse , endocrinology , medicine , fgf21 , sod1 , superoxide dismutase , fatty liver , chemistry , nonalcoholic fatty liver disease , lipid metabolism , biology , oxidative stress , fibroblast growth factor , receptor , disease
Superoxide dismutase‐1 (SOD1) is a well‐known intracellular antioxidant enzyme, and our laboratory has been studying impact and mechanism of the SOD1 knockout on glucose and lipid metabolism in mice. Non‐alcoholic fatty liver disease begins with an excessive accumulation of triglyceride in the liver, a condition that can eventually leads to hepatocyte injury, fibrosis, steatohepatitis, and cirrhosis. In the present study, we found hepatic triglyceride in the SOD1 knockout mice two‐fold higher (P < 0.05, n = 6) than that of their wild‐type controls starting at 3‐wk of age. Hepatic expression of more than 70 key genes related to responses or regulations of oxidative and endoplasmic reticular stresses, glucocorticoid receptor, casein kinase, Wnt, transforming growth factor‐β, caspase 1, and lipid metabolism was compared between the knockout and wildtype mice. Approximately one‐third of these genes were altered (P < 0.05) by the SOD1 knockout over the wild‐type control. Strikingly, the change of fibroblast growth factor‐21 (FGF21) ranked the highest among all the affected genes by the knockout. To determine if there was a cause‐effect relationship between the SOD1 knockout and the change in hepatic FGF21 mRNA levels, we treated primary hepatocytes isolated from the wild‐type mice with the SOD inhibitor (diethyl‐dithio‐carbamic acid at 0 and 50 μM for 6, 12 and 24 h), and found a four‐fold increase (P < 0.05) in FGF21 mRNA level due to the treatment. Subsequently, we injected (intraperitoneal) the SOD1 knockout mice (n = 12, male, 3‐wk old) with the SOD mimic [copper (II) 3, 5‐diisopropylsalicylate hydrate, 30 mg/kg body weight] every other day for 1 wk. The mimic injection resulted in a down‐regulation (P < 0.05) of hepatic FGF21 mRNA compared with the vehicle (80% Phosphate‐buffered saline, 10% Dimethyl sulfoxide and 10% Tween‐80) injection. In conclusion, knockout of SOD1 led to a substantial overexpression of the hepatic FGF21 mRNA, which may serve as one of the mechanisms for the development of non‐alcoholic fatty liver disease in the knockout mice. Support or Funding Information Supported in part by a NIH grant DK53018.