Stimulation of Fat Oxidation, but no Sustained Reduction of Hepatic Lipids by Prolonged Pharmacological Inhibition of Acetyl CoA Carboxylase

Abstract

Acetyl CoA carboxylase isoforms 1 and 2 (ACC1/2) are key enzymes of fat metabolism and their inhibition has been postulated to be beneficial for the treatment of the metabolic syndrome by decreasing ectopic fat accumulation. In order to validate this approach pharmacologically, we characterized the chronic effect of the small molecule ACC1/2 inhibitor SAR210 in 2 rodent models of fatty liver. Chronic administration of SAR210 increased serum ketone levels in both diet-induced obese mice and female ZDF rats. The inhibitor neither reduced hepatic triglycerides nor influenced body weight in either diet-induced obese mice or female ZDF rats. Thus, chronic pharmacological inhibition of ACC1/2 stimulated fat oxidation, which was, however, not sufficient to reduce hepatic triglycerides.

Key words

diabetes - fat metabolism - insulin - liver metabolism - metabolic syndrome

*

^* These authors contributed equally to this work.

• References

• 1 Wakil SJ, Abu-Elheiga LA. Fatty acid metabolism: target for metabolic syndrome. J Lipid Res 2009; 50 (Suppl) S138-S143
• 2 Corbett JW. Review of recent acetyl-CoA carboxylase inhibitor patents: mid-2007–2008. Expert Opin Ther Pat 2009; 19: 943-956
• 3 Harwood Jr HJ, Petras SF, Shelly LD, Zaccaro LM, Perry DA, Makowski MR, Hargrove DM, Martin KA, Tracey WR, Chapman JG, Magee WP, Dalvie DK, Soliman VF, Martin WH, Mularski CJ, Eisenbeis SA. Isozyme-nonselective N-substituted bipiperidylcarboxamide acetyl-CoA carboxylase inhibitors reduce tissue malonyl-CoA concentrations, inhibit fatty acid synthesis, and increase fatty acid oxidation in cultured cells and in experimental animals. J Biol Chem 2003; 278: 37099-37111
• 4 Roden M. Mechanisms of Disease: hepatic steatosis in type 2 diabetes – pathogenesis and clinical relevance. Nat Clin Pract Endocrinol Metab 2006; 2: 335-348
• 5 Shibata M, Kihara Y, Taguchi M, Tashiro M, Otsuki M. Nonalcoholic fatty liver disease is a risk factor for type 2 diabetes in middle-aged Japanese men. Diabetes Care 2007; 30: 2940-2944
• 6 Stefan N, Kantartzis K, Häring HU. Causes and metabolic consequences of Fatty Liver. Endocr Rev 2008; 29: 939-960
• 7 Savage DB, Choi CS, Samuel VT, Liu ZX, Zhang D, Wang A, Zhang XM, Cline GW, Yu XX, Geisler JG, Bhanot S, Monia BP, Shulman GI. Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2. J Clin Invest 2006; 116: 817-824
• 8 Harada N, Oda Z, Hara Y, Fujinami K, Okawa M, Ohbuchi K, Yonemoto M, Ikeda Y, Ohwaki K, Aragane K, Tamai Y, Kusunoki J. Hepatic de novo lipogenesis is present in liver-specific ACC1-deficient mice. Mol Cell Biol 2007; 27: 1881-1888
• 9 Choi CS, Savage DB, Abu-Elheiga L, Liu ZX, Kim S, Kulkarni A, Distefano A, Hwang YJ, Reznick RM, Codella R, Zhang D, Cline GW, Wakil SJ, Shulman GI. Continuous fat oxidation in acetyl-CoA carboxylase 2 knockout mice increases total energy expenditure, reduces fat mass, and improves insulin sensitivity. Proc Natl Acad Sci USA 2007; 104: 16480-16485
• 10 Hoehn KL, Turner N, Swarbrick MM, Wilks D, Preston E, Phua Y, Joshi H, Furler SM, Larance M, Hegarty BD, Leslie SJ, Pickford R, Hoy AJ, Kraegen EW, James DE, Cooney GJ. Acute or chronic upregulation of mitochondrial fatty acid oxidation has no net effect on whole-body energy expenditure or adiposity. Cell Metab 2010; 11: 70-76
• 11 Olson DP, Pulinilkunnil T, Cline GW, Shulman GI, Lowell BB. Gene knockout of ACC2 has little effect on body weight, fat mass, or food intake. Proc Natl Acad Sci USA 2010; 107: 7598-7603
• 12 Keil S, Müller M, Zoller G, Haschke G, Schroeter K, Glien M, Ruf S, Focken I, Herling AW, Schmoll D. Identification and Synthesis of Novel Inhibitors of Acetyl-CoA Carboxylase with in Vitro and in Vivo Efficacy on Fat Oxidation. J Med Chem 2010; 53: 8679-8687
• 13 Minkler PE, Kerner J, Ingalls ST, Hoppel CL. Novel isolation procedure for short-, medium-, and long-chain acyl-coenzyme A esters from tissue. Anal Biochem 2008; 376: 275-276
• 14 Herling AW, Burger HJ, Schubert G, Hemmerle H, Schäfer HL, Kramer W. Alteration of carbohydrate and lipid intermediary metabolism during inhibition of glucose-6-phosphatase in rats. Eur J Pharmacol 1999; 386: 75-82
• 15 Mao J, DeMayo FJ, Li H, Abu-Elheiga L, Gu Z, Shaikenov TE, Kordari P, Chirala SS, Heird WC, Wakil SJ. Liver-specific deletion of acetyl-CoA carboxylase 1 reduces hepatic triglyceride accumulation without affecting glucose homeostasis. Proc Natl Acad Sci USA 2006; 103: 8552-8557
• 16 Pfeiffer AFH. Adipose tissue and diabetes therapy: do we hit the target?. Horm Metab Res 2007; 39: 734-738
• 17 Miles JM, Nelson RH. Contribution of triglyceride-rich lipoproteins to plasma free fatty acids. Horm Metab Res 2007; 39: 726-729
• 18 Haschke G Unpublished data
• 19 Schreurs M, van Dijk TH, Gerding A, Havinga R, Reijngoud DJ, Kuipers F. Soraphen, an inhibitor of the acetyl-CoA carboxylase system, improves peripheral insulin sensitivity in mice fed a high-fat diet. Diabetes Obes Metab 2009; 11: 987-991