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Thioesterase superfamily member 2 (Them2) Regulates Fatty Acid Partitioning Between Oxidative and Secretory Pathways in the Liver
Author(s) -
AlvesBezerra Michele,
Li Yingxia,
Cohen David E.
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.672.5
Subject(s) - lipogenesis , medicine , endocrinology , triglyceride , fatty acid , beta oxidation , chemistry , adipose tissue , glucose homeostasis , fatty liver , metabolism , biology , biochemistry , cholesterol , insulin resistance , diabetes mellitus , disease
Them2 (synonym: Acyl‐CoA thioesterase 13) is a mitochondria‐associated long‐chain acyl‐CoA thioesterase that is abundant in the liver and oxidative tissues. Evidence from whole‐body knockout mice suggests that Them2 prevents diet‐induced hepatosteatosis and improves hepatic glucose homeostasis. In cultured hepatocytes, Them2 promotes fatty acid oxidation and decreases lipogenesis. However, because it also suppresses thermogenesis in brown adipose tissue by limiting fatty acid oxidation, the true contribution to fatty acid metabolism of Them2 in the liver remains unclear. In order to evaluate the role of Them2 in liver to fatty acid metabolism, we created Them2 liver‐specific knockout ( L‐Them2 −/− ) mice, which were fed chow or high fat diet for 12 weeks. L‐Them2 −/− mice exhibited similar weight gain, body mass composition and glucose homeostasis in comparison to control animals. Whereas the rates of fatty acid uptake, de novo fatty acid synthesis, and hepatic concentrations of free fatty acids were unchanged, hepatic fatty acid oxidation was increased by 30% in chow‐fed L‐Them2 −/− mice. In the absence of changes in steady concentrations of hepatic triglyceride and glycerolipid synthetic rates, a reduction in plasma triglyceride concentrations was observed upon hepatic Them2 ablation (38 and 43% decrease in chow and high fat fed, respectively). This was associated with a reduction in plasma VLDL‐triglyceride concentrations (29 and 9% in chow and high fat fed mice, respectively). Chow fed L‐Them2 −/− mice also exhibited a 26% reduction in plasma apoB100 concentrations and a marked (70%) reduction in hepatic VLDL‐triglyceride secretion rates. Taken together, these data suggest that hepatic Them2 functions to direct fatty acids towards triglyceride incorporation into VLDL particles for secretion and away from mitochondrial β‐oxidation, thereby sustaining the export of lipids from the liver to the plasma and peripheral tissues. We speculate that Them2 in the liver plays a key role in determining the metabolic fates of fatty acids in response to nutritional status and metabolic demands. Support or Funding Information This work was supported by NIH R37 DK048873 and R01 DK056626 to D.E.C. M.A.‐B. was the recipient of a NASH Fatty Liver Disease Postdoctoral Research Fellowship Award from the American Liver Foundation. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .