Metabolic pathways promoting intrahepatic fatty acid accumulation in methionine and choline deficiency: implications for the pathogenesis of steatohepatitis

Macfarlane DP, Zou X, Andrew R, Morton NM, Livingstone DE, Aucott RL, Nyirenda MJ, Iredale JP, Walker BR. Metabolic pathways promoting intrahepatic fatty acid accumulation in methionine and choline deficiency: implications for the pathogenesis of steatohepatitis. Am J Physiol Endocrinol Metab 300: E402-E409, 2011. First published November 30, 2010; doi: 10.1152/ajpendo.00331.2010.-The pathological mechanisms that distinguish simple steatosis from steatohepatitis (or NASH, with consequent risk of cirrhosis and hepatocellular cancer) remain incompletely defined. Whereas both a methionine-and choline-deficient diet (MCDD) and a choline-deficient diet (CDD) lead to hepatic triglyceride accumulation, MCDD alone is associated with hepatic insulin resistance and inflammation (steatohepatitis). We used metabolic tracer techniques, including stable isotope ([C-13(4)]palmitate) dilution and mass isotopomer distribution analysis (MIDA) of [C-13(2)] acetate, to define differences in intrahepatic fatty acid metabolism that could explain the contrasting effect of MCDD and CDD on NASH in C57Bl6 mice. Compared with control-supplemented (CS) diet, liver triglyceride pool sizes were similarly elevated in CDD and MCDD groups (24.37 +/- 2.4, 45.94 +/- 3.9, and 43.30 +/- 3.5 mu mol/liver for CS, CDD, and MCDD, respectively), but intrahepatic neutrophil infiltration and plasma alanine aminotransferase (31 +/- 3, 48 +/- 4, 231 +/- 79 U/l, P < 0.05) were elevated only in MCDD mice. However, despite loss of peripheral fat in MCDD mice, neither the rate of appearance of palmitate (27.2 +/- 3.5, 26.3 +/- 2.3, and 28.3 +/- 3.5 mu mol.kg(-1).min(-1)) nor the contribution of circulating fatty acids to the liver triglyceride pool differed between groups. Unlike CDD, MCDD had a defect in hepatic triglyceride export that was confirmed using intravenous tyloxapol (142 +/- 21, 122 +/- 15, and 80 +/- 7 mg.kg(-1).h(-1), P < 0.05). Moreover, hepatic de novo lipogenesis was significantly elevated in the MCDD group only (1.4 +/- 0.3, 2.3 +/- 0.4, and 3.4 +/- 0.4 mu mol/day, P < 0.01). These findings suggest that important alterations in hepatic fatty acid metabolism may promote the development of steatohepatitis. Similar mechanisms may predispose to hepatocyte damage in human NASH.