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Lipoic acid improves hypertriglyceridemia by stimulating triacylglycerol clearance and downregulating liver triacylglycerol secretion.

ABSTRACT: Elevated blood triacylglycerol (TG) is a significant contributing factor to the current epidemic of obesity-related health disorders, including type-2 diabetes, nonalcoholic fatty liver disease, and cardiovascular disease. The observation that mice lacking the enzyme sn-glycerol-3-phosphate acyltransferase are protected from insulin resistance suggests the possibility that the regulation of TG synthesis be a target for therapy. Five-week-old Zucker Diabetic Fatty (ZDF) rats were fed a diet containing (R)-alpha-lipoic acid (LA, approximately 200mg/kg body weight per day) for 5 weeks. LA offset the rise in blood and liver TG by inhibiting liver lipogenic gene expression (e.g. sn-glycerol-3-phosphate acyltransferase-1 and diacylglycerol O-acyltransferase-2), lowering hepatic TG secretion, and stimulating clearance of TG-rich lipoproteins. LA-induced TG lowering was not due to the anorectic properties of LA, as pair-fed rats developed hypertriglyceridemia. Livers from LA-treated rats exhibited elevated glycogen content, suggesting dietary carbohydrates were stored as glycogen rather than becoming lipogenic substrate. Although AMP-activated protein kinase (AMPK) reportedly mediates the metabolic effects of LA in rodents, no change in AMPK activity was observed, suggesting LA acted independently of this kinase. The hepatic expression of peroxisome proliferator activated receptor alpha (PPARalpha) target genes involved in fatty acid beta-oxidation was either unchanged or decreased with LA, indicating a different mode of action than for fibrate drugs. Given its strong safety record, LA may have potential clinical applications for the treatment or prevention of hypertriglyceridemia and diabetic dyslipidemia.

SUBMITTER: Butler JA

PROVIDER: S-EPMC2771166 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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Lipoic acid improves hypertriglyceridemia by stimulating triacylglycerol clearance and downregulating liver triacylglycerol secretion.

Butler Judy A JA Hagen Tory M TM Moreau Régis R

Archives of biochemistry and biophysics 20090220 1

Elevated blood triacylglycerol (TG) is a significant contributing factor to the current epidemic of obesity-related health disorders, including type-2 diabetes, nonalcoholic fatty liver disease, and cardiovascular disease. The observation that mice lacking the enzyme sn-glycerol-3-phosphate acyltransferase are protected from insulin resistance suggests the possibility that the regulation of TG synthesis be a target for therapy. Five-week-old Zucker Diabetic Fatty (ZDF) rats were fed a diet conta ...[more]

PMID: 19232511

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Project description:Context:Glucagon-like peptide-1 (GLP-1) agonists control postprandial glucose and lipid excursion in type 2 diabetes; however, the mechanisms are unclear. Objective:To determine the mechanisms of postprandial lipid and glucose control with lixisenatide (GLP-1 analog) in type 2 diabetes. Design:Randomized, double-blind, cross-over study. Setting:Centre for Diabetes, Endocrinology, and Research, Royal Surrey County Hospital, Guildford, United Kingdom. Patients:Eight obese men with type 2 diabetes [age, 57.3 ± 1.9 years; body mass index, 30.3 ± 1.0 kg/m2; glycosylated hemoglobin, 66.5 ± 2.6 mmol/mol (8.2% ± 0.3%)]. Interventions:Two metabolic studies, 4 weeks after lixisenatide or placebo, with cross-over and repetition of studies. Main Outcome Measures:Study one: very-low-density lipoprotein (VLDL) and chylomicron (CM) triacylglycerol (TAG) kinetics were measured with an IV bolus of [2H5]glycerol in a 12-hour study, with hourly feeding. Oral [13C]triolein, in a single meal, labeled enterally derived TAG. Study two: glucose kinetics were measured with [U-13C]glucose in a mixed-meal (plus acetaminophen to measure gastric emptying) and variable IV [6,6-2H2]glucose infusion. Results:Study one: CM-TAG (but not VLDL-TAG) pool-size was lower with lixisenatide (P = 0.046). Lixisenatide reduced CM [13C]oleate area under the curve (AUC)60-480min concentration (P = 0.048) and increased CM-TAG clearance, with no effect on CM-TAG production rate. Study two: postprandial glucose and insulin AUC0-240min were reduced with lixisenatide (P = 0.0051; P < 0.05). Total glucose production (P = 0.015), rate of glucose appearance from the meal (P = 0.0098), and acetaminophen AUC0-360min (P = 0.006) were lower with lixisenatide than with placebo. Conclusions:Lixisenatide reduced [13C]oleate concentrations, derived from a single meal in CM-TAG and glucose rate of appearance from the meal through delayed gastric emptying. However, day-long CM production, measured with repeated meal feeding, was not reduced by lixisenatide and decreased CM-TAG concentration resulted from increased CM-TAG clearance.

Dataset Information

Lipoic acid improves hypertriglyceridemia by stimulating triacylglycerol clearance and downregulating liver triacylglycerol secretion.

Publications

Lipoic acid improves hypertriglyceridemia by stimulating triacylglycerol clearance and downregulating liver triacylglycerol secretion.

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