title: Acetyl-CoA carboxylase 2-/- mutant mice are protected against fatty liver under high-fat, high-carbohydrate dietary and de novo lipogenic conditions.
abstract: Hepatic fat accumulation resulting from increased de novo fatty acid synthesis leads to hepatic steatosis and hepatic insulin resistance. We have shown previously that acetyl-CoA carboxylase 2 (Acc2(-/-)) mutant mice, when fed a high-fat (HF) or high-fat, high-carbohydrate (HFHC) diet, are protected against diet-induced obesity and maintained whole body and hepatic insulin sensitivity. To determine the effect of an ACC2 deletion on hepatic fat metabolism, we studied the regulation of the enzymes involved in the lipogenic pathway under Western HFHC dietary and de novo lipogenic conditions. After completing the HFHC regimen, Acc2(-/-) mutant mice were found to have lower body weight, smaller epididymal fat pads, lower blood levels of nonesterified fatty acids and triglycerides, and higher hepatic cholesterol than wild-type mice. Significant up-regulation of lipogenic enzymes and an elevation in hepatic peroxisome proliferator-activated receptor-γ (PPAR-γ) protein were found in Acc2(-/-) mutant mice under de novo lipogenic conditions. The increase in lipogenic enzyme levels was accompanied by up-regulation of the transcription factors, sterol regulatory element-binding proteins 1 and 2, and carbohydrate response element-binding protein. In contrast, hepatic levels of the PPAR-γ and PPAR-α proteins were significantly lower in the Acc2(-/-) mutant mice fed an HFHC diet. When compared with wild-type mice fed the same diet, Acc2(-/-) mutant mice exhibited a similar level of AKT but with a significant increase in pAKT. Hence, deleting ACC2 ameliorates the metabolic syndrome and protects against fatty liver despite increased de novo lipogenesis and dietary conditions known to induce obesity and diabetes.
authors.affiliation: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Lutfi
authors.initials: L
authors.lastname: Abu-Elheiga
authors.forename: Hongmei
authors.initials: H
authors.lastname: Wu
authors.forename: Ziwei
authors.initials: Z
authors.lastname: Gu
authors.forename: Rubin
authors.initials: R
authors.lastname: Bressler
authors.forename: Salih J
authors.initials: SJ
authors.lastname: Wakil
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000235:genetics* / Q000378:metabolism; D050154:Adiposity; D000818:Animals; D001056:Apolipoproteins C / Q000378:metabolism; D001786:Blood Glucose; D001835:Body Weight; D059305:Diet, High-Fat / Q000009:adverse effects*; D004040:Dietary Carbohydrates / Q000009:adverse effects*; D005215:Fasting; D064429:Fatty Acid Synthases / Q000378:metabolism; D005234:Fatty Liver / Q000097:blood / Q000201:enzymology* / Q000209:etiology; D005786:Gene Expression Regulation; D008055:Lipids / Q000097:blood; D050155:Lipogenesis; D008099:Liver / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D009929:Organ Size; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C484352:Apoc4 protein, mouse; D001056:Apolipoproteins C; D001786:Blood Glucose; D004040:Dietary Carbohydrates; D008055:Lipids; D014157:Transcription Factors; D064429:Fatty Acid Synthases; D051057:Proto-Oncogene Proteins c-akt; C498191:Acacb protein, mouse; D000103:Acetyl-CoA Carboxylase