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

Abstract

To investigate the cholesterol-lowering effectiveness of a phytosterol/α-lipoic acid (PS/αLA) therapy, thirty-two male Zucker rats were randomly assigned to 1 of 4 diets for 30 days: (i) high fat diet (HF, 40% energy from fat); (ii) HF diet supplemented with 3% phytosterols; (iii) HF diet supplemented with 0.25% αLA; or (iv) HF diet supplemented with PS (3%) and αLA (0.25%, PS/αLA). Compared with the HF diet, combination PS/αLA proved more effective in reducing non-HDL cholesterol (−55%) than either the PS (−24%) or the αLA (−25%) therapies alone. PS supplementation did not affect LDL particle number, however, αLA supplementation reduced LDL particle number when supplemented alone (−47%) or in combination with PS (−54%). Compared with the HF-fed animals, evidence of increased HDL-particle number was evident in all treatment groups to a similar extent (21–22%). PS-mediated interruption of intestinal cholesterol absorption was evident by increased fecal cholesterol loss (52%) and compensatory increase in HMG-CoA reductase mRNA (1.6 fold of HF), however, αLA supplementation did not affect fecal cholesterol loss. Hepatic mRNA and protein expression patterns suggested that αLA modulated multiple aspects of cholesterol homeostasis including reduced synthesis (HMG-CoA reductase mRNA, 0.7 fold of HF), reduced bile acid synthesis (CYP7a1 expression, 0.17 of HF), and increased cholesterol clearance (reduced PCSK9 mRNA, 0.5 fold of HF; increased LDLr protein, 2 fold of HF). Taken together, this data suggests that PS and αLA work through unique and complementary mechanisms to provide a superior and more comprehensive cholesterol lowering response than either therapy alone.

Transcriptional control of enterohepatic lipid regulatory targets in response to early cholesterol and phytosterol exposure in apoE−/− mice

“…This gene expression pattern may well reflect an effort to restore cholesterol lipid balance as cholesterol is critical for early development [ 43 ]. Although there are no other maternal PS supplementation studies with which to compare our gene expression data, previous PS supplementation studies in adult animals have reported variable expression of NCP1L1 [ 44 – 47 ] and a more consistent increase in HMG-CoAr expression [ 48 , 49 ] and cholesterol synthesis [ 50 – 52 ].…”

The Protective Effect of Lipoic Acid on Selected Cardiovascular Diseases Caused by Age-Related Oxidative Stress

“…Many animal and human studies report that LA supplementation can result in reduced cholesterol levels [ 89 , 90 ]. LA may also prevent LDL oxidation by reducing the concentrations of LDL-C, Ox-LDL, serum TC, and lipoprotein (a) [Lp(a)], as well as other oxidative biomarkers [ 85 ].…”

Chronic treatment of (R)‐α‐lipoic acid reduces blood glucose and lipid levels in high‐fat diet and low‐dose streptozotocin‐induced metabolic syndrome and type 2 diabetes in Sprague‐Dawley rats

“…; Rideout et al. ). ALA has also been shown to increase high‐density lipoprotein (HDL) cholesterol levels in high‐fat diet‐fed rats (Miao et al.…”

“…In addition, ALA has been shown to protect arterial lesion formation in vitro (Lee et al 2012). Conversely, no changes in serum total cholesterol and/or triglyceride levels were observed in streptozotocin-induced diabetic rats (Salama 2011) and in HFD-fed obese Zucker rats (Carrier et al 2014;Rideout et al 2016). ALA has also been shown to increase high-density lipoprotein (HDL) cholesterol levels in high-fat diet-fed rats (Miao et al 2013).…”