Alpha-Lipoic Acid Reduces LDL-Particle Number and PCSK9 Concentrations in High-Fat Fed Obese Zucker Rats

Abstract

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.

Does Alpha-Lipoic Acid Comsumption Improve Lipid Profile In Patients With Stroke? A Randomized, Double Blind, Placebo-Controlled Clinical Trial

“…Several animal (14,16) and human (17) studies have supported these finding even though none of them have reviewed the effect of ALA supplementation on lipid profile in patients with stroke. Consistent with the present study Carrier et al (14) examined the effects of ALA and its mechanism on lipid profile in high fat fed Zucker rats. In this study, rats were divided to 2 groups (a high fat diet or high fat diet with ALA for 30 days and pair fed to remove confounding effects of anti-appetite properties of ALA).…”

“…In addition, ALA protects the liver against TG accumulation via multiple mechanisms including: suppression of lipogenesis (down-regulation of hepatic acetyl-CoA carboxylase and fatty acid synthase expression); increase fat oxidation in liver (enhance carnitine palmitoyltransferase Ia expression); and increase export of VLDL (enhance hepatic diacylglycerol acyltransferase and microsomal triglyceride transfer protein expression and elevate number of plasma VLDL particles) (14,26,27). It is also reported that ALA enhances fatty acid uptake and oxidation in muscle tissue and is protective against increasing serum cholesterol and accumulating fat in liver under conditions of strong genetic and dietary predisposition toward obesity and dyslipidemia, without change in energy intake (4,14). In addition, it has been confirmed that ALA not only plays an important role in preventing fat accumulation (28,29) it even significantly reduces fat accumulation and appetite by regulating activities of central and peripheral adenosine monophosphate activated protein kinase (9,12,30).…”

“…However, beside these, it is indicated that with no change in energy intake, ALA could protect the liver against fat accumulation as well as hypercholesterolemia (14,15). Several animal (14,16) and human (17) studies have investigated possible effects of ALA on lipid profile and indicate various results. Carrier et al (14) examined the effects of ALA and its mechanism on lipid profile in high fat fed Zucker rats.…”

“…Several animal (14,16) and human (17) studies have investigated possible effects of ALA on lipid profile and indicate various results. Carrier et al (14) examined the effects of ALA and its mechanism on lipid profile in high fat fed Zucker rats. They observed that ALA could be protective against diet-induced obesity and hypercholesterolemia.…”

Complementary Cholesterol-Lowering Response of a Phytosterol/α-Lipoic Acid Combination in Obese Zucker Rats

“…The total body pool of αLA from synthesis and ingestion of dietary sources including muscle, heart, kidney, and liver is low; therefore, the purported health effects of αLA are only observed following dietary supplementation, which have been investigated in the broad range of 600–1800 mg/d [11]. Data from our laboratory has previously shown that reductions in LDL-cholesterol and LDL-particle number following αLA supplementation were associated with lower circulating concentrations of proprotein convertase subtilisin/kexin type 9 (PCSK9), a primary regulator of LDLr protein turnover [12]. αLA supplementation was recently shown to reduce atherosclerotic plaque formation by reducing aortic lipid and inflammatory cell infiltration in Watanabe heritable hyperlipidemic rabbits in the absence of any change in plasma lipids [13].…”