Metabolic pathways promoting intrahepatic fatty acid accumulation in methionine and choline deficiency: implications for the pathogenesis of steatohepatitis
| Autor: | Ruth Andrew, John P. Iredale, Xiantong Zou, Nicholas M. Morton, Moffat J. Nyirenda, Rebecca L. Aucott, David P. Macfarlane, Dawn E W Livingstone, Brian R. Walker |
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| Rok vydání: | 2011 |
| Předmět: |
nonalcoholic fatty liver disease
Male Physiology Endocrinology Diabetes and Metabolism Hepatitis Eating Mice chemistry.chemical_compound methionine- and choline-deficient diet Methionine 0302 clinical medicine Nonalcoholic fatty liver disease chemistry.chemical_classification 0303 health sciences Fatty Acids Fatty liver free fatty acids Articles Organ Size Immunohistochemistry Choline Deficiency 3. Good health choline-deficient diet Adipose Tissue Liver Lipogenesis 030211 gastroenterology & hepatology Metabolic Networks and Pathways medicine.medical_specialty steatohepatitis Palmitic Acids Biology Gas Chromatography-Mass Spectrometry 03 medical and health sciences Physiology (medical) Internal medicine medicine Animals Triglycerides 030304 developmental biology Triglyceride Fatty acid metabolism Fatty acid medicine.disease Diet Fatty Liver Mice Inbred C57BL Kinetics B vitamins de novo lipogenesis Endocrinology chemistry Hepatocytes Steatohepatitis |
| Zdroj: | American Journal of Physiology-Endocrinology and Metabolism |
| ISSN: | 1522-1555 0193-1849 |
| DOI: | 10.1152/ajpendo.00331.2010 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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