Alpha‐lipoic acid reduces LDL‐particle number and PCSK9 concentrations in high‐fat fed obese Zucker rats (829.14)

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