Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8260205 | Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | 2014 | 12 Pages |
Abstract
Methionine-choline-deficient (MCD) diet is a widely used dietary model of non-alcoholic steatohepatitis (NASH) in rodents. However, the contribution of adipose tissue to MCD-induced steatosis, and inflammation as features of NASH are not fully understood. The goal of this study was to elucidate the role of adipose tissue fatty acid (FA) metabolism, adipogenesis, lipolysis, inflammation and subsequent changes in FA profiles in serum and liver in the pathogenesis of steatohepatitis. We therefore fed ob/ob mice with control or MCD diet for 5Â weeks. MCD-feeding increased adipose triglyceride lipase and hormone sensitive lipase activities in all adipose depots which may be attributed to increased systemic FGF21 levels. The highest lipase enzyme activity was exhibited by visceral WAT. Non-esterified fatty acid (NEFA)-18:2n6 was the predominantly elevated FA species in serum and liver of MCD-fed ob/ob mice, while overall serum total fatty acid (TFA) composition was reduced. In contrast, an overall increase of all FA species from TFA pool was found in liver, reflecting the combined effects of increased FA flux to liver, decreased FA oxidation and decrease in lipase activity in liver. NAFLD activity score was increased in liver, while WAT showed no changes and BAT showed even reduced inflammation. Conclusion: This study demonstrates a key role for adipose tissue lipases in the pathogenesis of NASH and provides a comprehensive lipidomic profiling of NEFA and TFA homeostasis in serum and liver. Our findings provide novel mechanistic insights for the role of WAT in progression of MCD-induced liver injury.
Keywords
PCYT2DNLFGF21DGATCpt1βNEFAACC1SNSMCDSCD1HSLstearoyl-CoA desaturase-1BATPEMTUCP-1ATP5BCox4i1TFADiglyceride acyltransferasecell death-inducing DFFA-like effector aDocosapentaenoic acid (DPA)SREBP1cPPARγ2NAFLDACSL116:018:0C/EBPαCCAAT/enhancer-binding protein alphaAtglde novo lipogenesisNon-alcoholic steatohepatitisacetyl-CoA carboxylaseAdrenic acidArachidonic acidStearic acidOleic acidEicosapentaenoic acid (EPA)docosahexaenoic acidLinoleic acidLignoceric acidPalmitoleic acidFatty acidNon-esterified fatty acidstandard deviationImmunohistochemistryIHCbrown adipose tissuenon-alcoholic fatty liver diseasetriglyceridesympathetic nervous systemfibroblast growth factor 21phosphatidylethanolamine N-methyltransferaseadipose triglyceride lipasehormone sensitive lipaseLipolysisNash Vaccenic acidPalmitic aciduncoupling protein 1sterol regulatory element-binding protein 1cWATLiverTotal fatty acidCidea
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Authors
Pooja Jha, Astrid Knopf, Harald Koefeler, Michaela Mueller, Carolin Lackner, Gerald Hoefler, Thierry Claudel, Michael Trauner,