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      Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) stimulates VLDL assembly through activation of cell death-inducing DFFA-like effector B (CideB).

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          Abstract

          Abnormalities in very low density lipoprotein (VLDL) assembly and secretion impact intrahepatic lipid homeostasis, plasma lipoprotein profile, and energy metabolism of distal peripheral tissues. We have evaluated the role of the transcriptional coactivator, the peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha), in VLDL assembly and secretion. PGC-1alpha overexpression in HepG2 cells led to diminished rates of triglyceride (TG) synthesis but strongly stimulated VLDL-TG secretion, markedly increasing the efficiency of secretion of newly synthesized TG. PGC-1alpha overexpression increased the rate of secretion of apoB100 and promoted secretion of larger, less dense VLDL particles. PGC-1alpha overexpression in intact mouse liver also stimulated rates of VLDL TG secretion and attenuated hepatic TG accumulation resulting from high fat diet feeding. To determine the molecular mechanisms mediating the effect of PGC-1alpha on VLDL assembly, we evaluated the expression of several candidate mediators known to be involved in VLDL assembly or hepatic lipid homeostasis. Cell death-inducing DFFA-like effector B (CideB) expression was greatly induced by PGC-1alpha, and siRNA against CideB reversed the effects of PGC-1alpha on the secretion of TG and VLDL-sized particles by HepG2 cells, indicating that CideB is a critical mediator of stimulatory effects of PGC-1alpha on VLDL secretion. Collectively, these data suggest that PGC-1alpha plays an important role in partitioning cytoplasmic TG toward the VLDL secretory compartments and promoting VLDL secretion via transcriptional induction of CideB.

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          Author and article information

          Journal
          J. Biol. Chem.
          The Journal of biological chemistry
          American Society for Biochemistry & Molecular Biology (ASBMB)
          1083-351X
          0021-9258
          Aug 20 2010
          : 285
          : 34
          Affiliations
          [1 ] Division of Geriatrics and Nutritional Science, Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA. zchen23@wustl.edu
          Article
          M110.141598
          10.1074/jbc.M110.141598
          2923994
          20551328

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