한빛사 논문
Abstract
1Department of Internal Medicine
2Department of Pathology
3Department of Biochemistry, Chungnam National University School of Medicine, Daejeon 301-721, Korea
4Mazence Inc. R&D Center, Suwon 443-813, Korea
5Department of Environmental Health, Seoul Health College, Sungnam 461-713, Korea
6Department of Physiology and Biophysics, Inje University College of Medicine, Busan 614-735, Korea
7Hormone Research Center, Chonnam National University, Kwangju 500-757, Korea
8Section of Endocrinology, Department of Internal Medicine, Kyungpook National University School of Medicine, 50 Samduk-2Ga, Junggu, Daegu, 700-721, Korea
9Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea
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-1{alpha}, 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.
Correspondence: Gi Ryang Kweon9 and Minho Shong1논문정보
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