Abstract
The activation of hepatic kinase mechanistic target of rapamycin complex 1 (mTORC1) is implicated in the development of obesity-related metabolic disorders. This study investigated the metabolic sequelae of mTORC1 hyperactivation in human hepatoma cells and the lipid-regulating mechanisms of two short-chain fatty acids: 4-phenylbutyric acid (PBA) and (R)-α-lipoic acid (LA). We created three stable cell lines that exhibit low, normal, or high mTORC1 activity. mTORC1 hyperactivation induced the expression of lipogenic (DGAT1 and DGAT2) and lipoprotein assembly (MTP and APOB) genes, thereby raising cellular triacylglyceride (TG) and exacerbating secretion of apoB-containing TG-rich lipoproteins. LYS6K2, a specific inhibitor of the p70 S6 kinase branch of mTORC1 signaling, reversed these effects. PBA and LA decreased secreted TG through distinct mechanisms. PBA repressed apoB expression (both mRNA and protein) and lowered secreted TG without mitigation of mTORC1 hyperactivity or activation of AMPK. LA decreased cellular and secreted TG by attenuating mTORC1 signaling in an AMPK-independent manner. LA did not regulate apoB expression but led to the secretion of apoB-containing TG-poor lipoproteins by repressing the expression of lipogenic genes, FASN, DGAT1, and DGAT2. Our studies provide new mechanistic insight into the hypolipidemic activity of PBA and LA in the context of mTORC1 hyperactivation and suggest that the short-chain fatty acids may aid in the prevention and treatment of hypertriglyceridemia.
Keywords:
AMP-activated protein kinase; LYS6K2; Rapamycin; Tuberous sclerosis complex; VLDL; apoE.
Copyright © 2015 Elsevier B.V. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Apolipoprotein B-100 / genetics
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Apolipoprotein B-100 / metabolism*
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Carcinoma, Hepatocellular / genetics
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Carcinoma, Hepatocellular / metabolism*
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Carcinoma, Hepatocellular / pathology
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Diacylglycerol O-Acyltransferase / genetics
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Diacylglycerol O-Acyltransferase / metabolism
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Fatty Acid Synthase, Type I / genetics
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Fatty Acid Synthase, Type I / metabolism
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Hep G2 Cells
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Humans
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Hypertriglyceridemia / drug therapy*
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Hypertriglyceridemia / genetics
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Hypertriglyceridemia / metabolism
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Liver Neoplasms / enzymology*
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Liver Neoplasms / genetics
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Liver Neoplasms / pathology
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Mechanistic Target of Rapamycin Complex 1
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Multiprotein Complexes / antagonists & inhibitors
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Multiprotein Complexes / genetics
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Multiprotein Complexes / metabolism*
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Phenylbutyrates / pharmacology*
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Protein Kinase Inhibitors / pharmacology
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RNA Interference
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Regulatory-Associated Protein of mTOR
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TOR Serine-Threonine Kinases / antagonists & inhibitors
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TOR Serine-Threonine Kinases / genetics
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TOR Serine-Threonine Kinases / metabolism*
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Thioctic Acid / pharmacology*
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Transfection
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Triglycerides / metabolism*
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
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Up-Regulation
Substances
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APOB protein, human
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Adaptor Proteins, Signal Transducing
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Apolipoprotein B-100
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Carrier Proteins
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Multiprotein Complexes
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Phenylbutyrates
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Protein Kinase Inhibitors
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RPTOR protein, human
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Regulatory-Associated Protein of mTOR
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Triglycerides
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins
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microsomal triglyceride transfer protein
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Thioctic Acid
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4-phenylbutyric acid
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DGAT1 protein, human
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DGAT2 protein, human
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Diacylglycerol O-Acyltransferase
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FASN protein, human
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Fatty Acid Synthase, Type I
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Mechanistic Target of Rapamycin Complex 1
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TOR Serine-Threonine Kinases