Abstract
The constitutive activation of the mechanistic target of rapamycin complex 1 (mTORC1) leads to the overproduction of apoB-containing triacylglycerol-rich lipoproteins in HepG2 cells. R-α-lipoic acid (LA) and 4-phenylbutyric acid (PBA) have hypolipidemic function but their mechanisms of action are not well understood. Here, we reported that LA and PBA regulate hepatocellular lipid metabolism via distinct mechanisms. The use of SQ22536, an inhibitor of adenylyl cyclase, revealed cAMP’s involvement in the upregulation of CPT1A expression by LA but not by PBA. LA decreased the secretion of proprotein convertase subtilisin/kexin type 9 (PCSK9) in the culture media of hepatic cells and increased the abundance of LDL receptor (LDLR) in cellular extracts in part through transcriptional upregulation. Although PBA induced LDLR gene expression, it did not translate into more LDLR proteins. PBA regulated cellular lipid homeostasis through the induction of CPT1A and INSIG2 expression via an epigenetic mechanism involving the acetylation of histone H3, histone H4, and CBP-p300 at the CPT1A and INSIG2 promoters.
Highlights
The association between LDL cholesterol (LDL-C) and coronary heart disease (CHD)risk is prominent in observational studies and clinical trials, the attention to elevated triacylglycerides (TAG) and low high-density lipoprotein (HDL) cholesterol (HDL-C) has increased with respect to risk estimation and therapeutic targets for intervention [1]
We created three stable HepG2 cell lines in which mechanistic target of rapamycin complex 1 (mTORC1) activity is normal, low, or high and demonstrated that application of lipoic acid (LA) or phenylbutyric acid (PBA) in shTSC2 cells led to a significant lowering of VLDL-like particle secretion [40]
We examined the lipid-lowering properties of LA and PBA in all three HepG2 cell lines based on changes in expression of genes involved in lipolysis, lipogenesis, TAG synthesis, and lipoprotein assembly
Summary
The association between LDL cholesterol (LDL-C) and coronary heart disease (CHD). Risk is prominent in observational studies and clinical trials, the attention to elevated triacylglycerides (TAG) and low HDL cholesterol (HDL-C) has increased with respect to risk estimation and therapeutic targets for intervention [1]. Owing to the metabolic interconnection between TAG-rich lipoproteins, HDL and insulin resistance, hypertriglyceridemia is frequently observed in combination with low HDL-C and type 2 diabetes. LDL-C/HDL-C ratio have a disproportionately higher risk of CHD events [2,3]. Hypertriglyceridemia, which affects ~30% of U.S adults [4], is defined as fasting blood TAG levels above 150 mg/dL (~1.8 mM).
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