Abstract
Alpha‐lipoic acid (LA) possesses hypocholesterolemic properties; however, the underlying molecular mechanisms have not been fully elucidated. We examined the effects of LA supplementation on blood cholesterol, lipoprotein distribution, and hepatic cholesterol homeostasis in a high fat fed Zucker rat model driven by both a genetic predisposition and diet induction toward obesity and dyslipidemia. Rats (n=8) were assigned to a high fat (HF) diet or the HF diet with 0.25% LA (HF‐LA) for 30 days. LA‐supplementation protected against diet‐induced obesity (102.5±3.1 vs. 121.5± 3.6, % change BW), reduced plasma total‐C (11%), non‐HDL‐C (25%) and LDL particle number (46%) and increased HDL particle number (22%) compared with the HF group. Hepatic cholesterol concentration did not differ between the HF and HF‐LA groups. LA supplementation reduced the mRNA expression of HMG‐CoAr (0.7 fold of HF) and enhanced the protein abundance of LDLr (2 fold of HF) and nuclear SREBP2 (3 fold of HF). LA supplementation was also associated with a reduction in hepatic PCSK9 mRNA (0.5 fold of HF) and serum PCSK9 concentration (70%), a primary regulator of LDLr turnover. Study results suggest that LA supplementation protects against hypercholesterolemia through a mechanism that involves modulation of PCSK9 activity and hepatic LDL‐C clearance.Grant Funding Source: Supported by a grant from the National Center for Complementary and Alternative Medicine
Highlights
Obesity, with a prevalence of over 35% in American adults and 16.9% in children and adolescence, is considered the most critical threat to the health and well being of Americans [1,2]
lipoic acid (LA) consumption reduced (p,0.05) total low-density lipoprotein (LDL) particle number (247%), a consequence of reductions in both large (234%) and intermediate (281%) LDL particles compared with the high fat (HF) animals (Fig. 2B)
Using a Zucker rat model driven by both a genetic predisposition and diet induction toward obesity and dyslipidemia, results of this study expands the current knowledge base regarding the protective properties of LA with several novel observations
Summary
With a prevalence of over 35% in American adults and 16.9% in children and adolescence, is considered the most critical threat to the health and well being of Americans [1,2]. Blood lipid abnormalities in obese, insulin resistant individuals, including increased TG and small dense low-density lipoprotein (LDL) particles, are directly and indirectly linked with the inability of peripheral and hepatic tissues to respond to the normal actions of insulin in regulating fatty acid storage and lipoprotein assembly [5]. Weight reduction through significant and sustained lifestyle modifications in diet and exercise is effective in improving insulin resistance and the associated metabolic disturbances, there exist limited nutraceutical options recognized to protect against dyslipidemia and hepatic steatosis. The purpose of this study was to evaluate the protective effects of LA on blood lipids and lipoproteins and seek the underlying mechanism by examining gene/protein expression of hepatic regulators of cholesterol metabolism and de novo lipogenesis, fatty acid oxidation, and lipoprotein assembly. As crosstalk between genetics and dietary factors influence the development of obesity and associated dyslipidemia, we chose to test the efficacy of LA under the influence of strong genetic and dietary predisposition to obesity and dyslipidemia with the use of high fat-fed Zucker rats, independent of changes in feed or caloric intake induced by LA
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