Metabolic pathways promoting intrahepatic fatty acid accumulation in methionine and choline deficiency: implications for the pathogenesis of steatohepatitis.
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 ([¹³C₄]palmitate) dilution and mass isotopomer distribution analysis (MIDA) of [¹³C₂]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 μmol/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 μmol·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 μmol/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.
University/BHF Centre for Cardiovascular Science, University of Edinburgh, United Kingdom.
David P
DP
Macfarlane
Xiantong
X
Zou
Ruth
R
Andrew
Nicholas M
NM
Morton
Dawn E W
DE
Livingstone
Rebecca L
RL
Aucott
Moffat J
MJ
Nyirenda
John P
JP
Iredale
Brian R
BR
Walker
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D002796:Choline Deficiency / Q000378:metabolism*; D004032:Diet; D004435:Eating / Q000502:physiology; D005227:Fatty Acids / Q000378:metabolism*; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology; D008401:Gas Chromatography-Mass Spectrometry; D006505:Hepatitis / Q000378:metabolism; D022781:Hepatocytes / Q000473:pathology; D007150:Immunohistochemistry; D007700:Kinetics; D050155:Lipogenesis / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D008297:Male; D053858:Metabolic Networks and Pathways; D008715:Methionine / Q000172:deficiency*; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size / Q000502:physiology; D010169:Palmitic Acids / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
D005227:Fatty Acids; D010169:Palmitic Acids; D014280:Triglycerides; D008715:Methionine