title: 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.
authors.affiliation: Departments of Exercise and Nutrition Sciences, School of Public Health and Health Professions, University at Buffalo, Buffalo, New York, United States of America.
authors.forename: Bradley
authors.initials: B
authors.lastname: Carrier
authors.affiliation: Departments of Exercise and Nutrition Sciences, School of Public Health and Health Professions, University at Buffalo, Buffalo, New York, United States of America.
authors.forename: Shin
authors.initials: S
authors.lastname: Wen
authors.affiliation: Departments of Exercise and Nutrition Sciences, School of Public Health and Health Professions, University at Buffalo, Buffalo, New York, United States of America.
authors.forename: Sophia
authors.initials: S
authors.lastname: Zigouras
authors.affiliation: Biotechnical and Clinical Laboratory Sciences, University at Buffalo, Buffalo, New York, United States of America.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Browne
authors.affiliation: Departments of Exercise and Nutrition Sciences, School of Public Health and Health Professions, University at Buffalo, Buffalo, New York, United States of America.
authors.forename: Zhuyun
authors.initials: Z
authors.lastname: Li
authors.affiliation: Biochemistry, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York, United States of America.
authors.forename: Mulchand S
authors.initials: MS
authors.lastname: Patel
authors.affiliation: Departments of Exercise and Nutrition Sciences, School of Public Health and Health Professions, University at Buffalo, Buffalo, New York, United States of America.
authors.forename: David L
authors.initials: DL
authors.lastname: Williamson
authors.affiliation: Departments of Exercise and Nutrition Sciences, School of Public Health and Health Professions, University at Buffalo, Buffalo, New York, United States of America.
authors.forename: Todd C
authors.initials: TC
authors.lastname: Rideout
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D059305:Diet, High-Fat / Q000009:adverse effects; D002149:Energy Intake / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000097:blood / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009765:Obesity / Q000097:blood / Q000378:metabolism / Q000517:prevention & control*; D000071449:Proprotein Convertase 9; D051381:Rats; D011924:Rats, Zucker; D012697:Serine Endopeptidases / Q000097:blood / Q000378:metabolism*; D008063:Thioctic Acid / Q000627:therapeutic use*; D014280:Triglycerides / Q000378:metabolism
chemical_list: D000975:Antioxidants; D008077:Lipoproteins, LDL; D014280:Triglycerides; D008063:Thioctic Acid; C510804:PCSK9 protein, rat; D000071449:Proprotein Convertase 9; D012697:Serine Endopeptidases