We characterized the hypolipidemic effects of alpha-lipoic acid (LA, R-form) and examined the associated molecular mechanisms in a high fat fed Zucker rat model. Rats (n = 8) were assigned to a high fat (HF) diet or the HF diet with 0.25% LA (HF-LA) for 30 days and pair fed to remove confounding effects associated with the anorectic properties of LA. Compared with the HF controls, the HF-LA group was protected against diet-induced obesity (102.5±3.1 vs. 121.5±3.6,% change BW) and hypercholesterolemia with a reduction in total-C (−21%), non-HDL-C (−25%), LDL-C (−16%), and total LDL particle number (−46%) and an increase in total HDL particles (∼22%). This cholesterol-lowering response was associated with a reduction in plasma PCSK9 concentration (−70%) and an increase in hepatic LDLr receptor protein abundance (2 fold of HF). Compared with the HF-fed animals, livers of LA-supplemented animals were protected against TG accumulation (−46%), likely through multiple mechanisms including: a suppressed lipogenic response (down-regulation of hepatic acetyl-CoA carboxylase and fatty acid synthase expression); enhanced hepatic fat oxidation (increased carnitine palmitoyltransferase Iα expression); and enhanced VLDL export (increased hepatic diacylglycerol acyltransferase and microsomal triglyceride transfer protein expression and elevated plasma VLDL particle number). Study results also support an enhanced fatty acid uptake (2.8 fold increase in total lipase activity) and oxidation (increased CPT1β protein abundance) in muscle tissue in LA-supplemented animals compared with the HF group. In summary, in the absence of a change in caloric intake, LA was effective in protecting against hypercholesterolemia and hepatic fat accumulation under conditions of strong genetic and dietary predisposition toward obesity and dyslipidemia.

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