A moderate increase in carnitine palmitoyltransferase 1a activity is sufficient to substantially reduce hepatic triglyceride levels

American Journal of Physiology - Endocrinology and Metabolism - Tập 294 Số 5 - Trang E969-E977 - 2008
Maja Stefanović-Račić1, Germán Perdomo, Benjamin S. Mantell, Ian Sipula, Nicholas F. Brown, Robert M. O’Doherty
1Department of Medicine, Division of Endocrinology, University of Pittsburg, Pittsburgh, PA, USA.

Tóm tắt

Nonalcoholic fatty liver disease (NAFLD), hypertriglyceridemia, and elevated free fatty acids are present in the majority of patients with metabolic syndrome and type 2 diabetes mellitus and are strongly associated with hepatic insulin resistance. In the current study, we tested the hypothesis that an increased rate of fatty acid oxidation in liver would prevent the potentially harmful effects of fatty acid elevation, including hepatic triglyceride (TG) accumulation and elevated TG secretion. Primary rat hepatocytes were transduced with adenovirus encoding carnitine palmitoyltransferase 1a (Adv-CPT-1a) or control adenoviruses encoding either β-galactosidase (Adv-β-gal) or carnitine palmitoyltransferase 2 (Adv-CPT-2). Overexpression of CPT-1a increased the rate of β-oxidation and ketogenesis by ∼70%, whereas esterification of exogenous fatty acids and de novo lipogenesis were unchanged. Importantly, CPT-1a overexpression was accompanied by a 35% reduction in TG accumulation and a 60% decrease in TG secretion by hepatocytes. There were no changes in secretion of apolipoprotein B (apoB), suggesting the synthesis of smaller, less atherogenic VLDL particles. To evaluate the effect of increasing hepatic CPT-1a activity in vivo, we injected lean or obese male rats with Adv-CPT-1a, Adv-β-gal, or Adv-CPT-2. Hepatic CPT-1a activity was increased by ∼46%, and the rate of fatty acid oxidation was increased by ∼44% in lean and ∼36% in obese CPT-1a-overexpressing animals compared with Adv-CPT-2- or Adv-β-gal-treated rats. Similar to observations in vitro, liver TG content was reduced by ∼37% (lean) and ∼69% (obese) by this in vivo intervention. We conclude that a moderate stimulation of fatty acid oxidation achieved by an increase in CPT-1a activity is sufficient to substantially reduce hepatic TG accumulation both in vitro and in vivo. Therefore, interventions that increase CPT-1a activity could have potential benefits in the treatment of NAFLD.

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Tài liệu tham khảo

10.1126/science.1056843

10.1073/pnas.1733877100

10.1038/nm995

10.1056/NEJMra011775

10.1016/S0091-679X(08)60603-2

10.1056/NEJMoa060326

10.1139/o59-099

10.1016/j.cld.2004.04.005

Brown NF.Expression, purification, and reconstitution of rat liver carnitine palmitoyltransferase I.Methods Mol Biol228: 281–301, 2003.

Brown NF, Esser V, Foster DW, McGarry JD.Expression of a cDNA for rat liver carnitine palmitoyltransferase I in yeast establishes that catalytic activity and malonyl-CoA sensitivity reside in a single polypeptide.J Biol Chem269: 26438–26442, 1994.

10.1042/bj2620425

10.1172/JCI200422422

10.1016/S0168-8278(99)80033-6

Davis RA, Clinton GM, Borchardt RA, Malone-McNeal M, Tan T, Lattier GR.Intrahepatic assembly of very low density lipoproteins. Phosphorylation of small molecular weight apolipoprotein B.J Biol Chem259: 3383–3386, 1984.

10.1016/S0016-5085(98)70599-2

10.1152/ajpendo.2002.282.1.E46

10.2337/diabetes.50.1.123

10.1073/pnas.0401627101

10.1042/bj3170791

10.1042/bj2490409

10.1016/j.bbalip.2004.06.005

10.1210/en.2005-0731

Hughes S.D, Quaade C, Johnson JH, Ferber S, Newgard CB.Transfection of AtT-20ins cells with GLUT-2 but not GLUT-1 confers glucose-stimulated insulin secretion. Relationship to glucose metabolism.J Biol Chem268: 15205–15212, 1993.

10.2337/diabetes.54.2.322

10.1152/ajpendo.00117.2003

10.1096/fasebj.3.11.2570725

10.1073/pnas.97.7.3450

10.2337/diabetes.50.8.1844

10.1053/jhep.2003.50161

10.1111/j.1432-1033.1997.00001.x

10.1172/JCI108764

10.1042/bj2140021

10.1073/pnas.132384699

10.1074/jbc.M403566200

10.1002/hep.1840380426

10.1042/bj3640219

10.1074/jbc.M313478200

10.1210/jcem.87.7.8638

10.1016/j.jhep.2005.10.033

10.1093/ajcn/81.1.35

Waugh DA, Small DM.Rapid method for determining cholesteryl ester transitions of apoB-containing lipoproteins.J Lipid Res23: 201–204, 1982.

Woeltje KF, Kuwajima M, Foster DW, McGarry JD.Characterization of the mitochondrial carnitine palmitoyltransferase enzyme system. II. Use of detergents and antibodies.J Biol Chem262: 9822–9827, 1987.

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American Journal of Physiology - Endocrinology and Metabolism

Tập 294 Số 5

E969-E977

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