Coenzyme A, acyl-CoA, and the glutathione system in CNS structures exposed to homopantothenate or in aluminum neurotoxicity

Abstract—Calcium homopantothenate (CHP, pantogam, or hopantenic acid) at a dose of 100 μg/kg was injected into white female Wistar rats weighing 180–210 g for 4 weeks. Aluminum chloride (two times at a dose of 190 mg/kg) and D pantenol (seven times at a dose of 200 mg/kg) were injected to a subgroup of rats during the last 2 weeks of the experiment. CHP did not change the level of coenzyme A (CoA) in the hippoc
ampus, brainstem, and cerebellum, while aluminum neurotoxicity resulted in a decrease in the CoA SH level in the hippocampus and acyl CoA level in the cerebellum. A decrease in glutathione level, redox status, and the total amount of glutathione and glutathione peroxidase activity was observed during aluminum neurotox icity. Both treatments activated glutathione reductase and decreased the activity of glucose 6 phosphate dehydrogenase in the brainstem. These changes were eliminated by pantenol. The latter increased the redox status of CNS proteins in the case of the combination of treatment with CHP and aluminum neurotoxicity.

Inhibition of Long-Chain Acyl Coenzyme A Synthetases During Fatty Acid Loading Induces Lipotoxicity in Macrophages

OBJECTIVE: Obesity is often associated with hypertriglyceridemia and elevated free fatty acids (FFAs), which are independent risk factors for cardiovascular disease and diabetes. Although impairment of cholesterol homeostasis is known to induce toxicity in macrophages, the consequence of altered fatty acid homeostasis is not clear. METHODS AND RESULTS: Long-chain acyl CoA synthetases (ACSLs) play a critical role in fatty acid homeostasis by channeling fatty acids to diverse metabolic pools. We treated mouse peritoneal macrophages (MPMs) with VLDL or FFAs in the presence of triacsin C, an inhibitor of the 3 ACSL isoforms present in macrophages. Treatment of macrophages with VLDL and triacsin C resulted in reduced TG accumulation but increased intracellular FFA levels, which induced lipotoxicity characterized by induction of apoptosis. Treatment of MPMs with the saturated fatty acid stearic acid in the presence of triacsin C increased intracellular stearic acid and induced apoptosis. Stromal vascular cells collected from high-fat diet-fed mice displayed foam cell morphology and exhibited increased mRNA levels of macrophage markers and ACSL1. Importantly, all of these changes were associated with increased FFA level in AT. CONCLUSIONS: Inhibition of ACSLs during fatty acid loading results in apoptosis via accumulation of FFAs. Our data have implications in understanding the consequences of dysregulated fatty acid metabolism in macrophages.

Saraswathi V, Hasty AH.
Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tenn

Pharmacological Stimulation of NADH Oxidation Ameliorates Obesity and Related Phenotypes in Mice

Objective Nicotinamide adenine dinucleotides (NAD+ and NADH) play a crucial role in cellular energy metabolism, and dysregulated NAD+/NADH ratio is implicated in metabolic syndrome. However, it is still unknown that modulating intracellular NAD+/NADH ratio is beneficial in treating metabolic syndrome. Thus, we tried to determine whether pharmacological stimulation of NADH oxidation provides therapeutic effects in rodent models of metabolic syndrome.

Research Design and Methods We used β-lapachone (βL), a natural substrate of NADH:quinone oxidoreductase 1 (NQO1), to stimulate NADH oxidation. The βL-induced pharmacological effect on cellular energy metabolism was evaluated in cells derived from NQO1-deficient mice. In vivo therapeutic effects of βL on metabolic syndrome were examined in diet-induced obesity (DIO) and ob/ob mice.

Results NQO1-dependent NADH oxidation by βL strongly provoked mitochondrial fatty acid oxidation in vitro and in vivo. These effects were accompanied with activation of AMP-activated protein kinase (AMPK) and carnitine palmitoyltransferase (CPT) and suppression of acetyl-CoA carboxylase (ACC) activity. Consistently, systemic βL administration in rodent models of metabolic syndrome dramatically ameliorated their key symptoms such as increased adiposity, glucose intolerance, dyslipidemia, and fatty liver. The treated mice also showed higher expressions of the genes related to mitochondrial energy metabolism (PGC-1α, NRF-1) and caloric restriction (Sirt1), consistent with the increased mitochondrial biogenesis and energy expenditure.

Conclusions Pharmacological activation of NADH oxidation by NQO1 resolves obesity and related phenotypes in mice, opening the possibility that it may provide the basis for a new therapy for the treatment of metabolic syndrome