Acetyl-CoA carboxylase 2-:- mutant mice are protected against fatty liver under high-fat, high-carb

Fatty acid synthesis is markedly increased under

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fatty acid synthesis is markedly increased under these pathological conditions as a result of the activation of transcrip- tion factors, such as sterol regulatory element-binding protein 1 (SREBP-1) and peroxisome proliferator-activated receptor (PPAR- ), in lipogenic tissues (11). As we have shown previously, Acc2 / mutant mice are pro- tected against obesity and type 2 diabetes as induced by an HFHC diet (12). We subsequently showed that because of con- tinuous fatty acid oxidation, Acc2 / mutant mice fed an HF diet were protected against fat-induced peripheral and hepatic insulin resistance (13). The improvement in insulin-stimulated glucose metabolism resulted in part from enhanced insulin sig- naling in the liver, as evidenced by a significant increase in insu- lin-induced repression of hepatic glucose production (13). Herein, we report our findings from a study of the effects of a chronic ACC2 deletion on liver lipogenesis in Acc2 / mutant mice under different dietary conditions. EXPERIMENTAL PROCEDURES Animals and Dietary Conditions —Male Acc2 / mutant and wild-type mice (Sv/129) were housed under controlled environmental conditions (12-h light/dark cycle; 25 °C temper- ature) in the Animal Care Center at Baylor College of Medicine. Animal experiments were conducted in accordance with the NIH guidelines (32). Five mice, either all Acc2 / mutants or all wild-type, were housed per cage and had free access to stan- dard laboratory chow (Purina Mills, Richmond, IN). To study the effects of an HFHC diet (59% of calories derived from fat and 24% from carbohydrates; Bioserv, Frenchtown, NJ), 3–4- month-old Acc2 / mutant mice were fed this diet for 2 months. To create lipogenic conditions, wild-type and Acc2 / mutant mice between 4 and 5 months of age underwent a 48-h fast and were subsequently fed an FFHC diet for 48 h. Under fasting conditions, food was removed for 48 h, and the mice had access to water only. Measurement of Blood Constituents —Whole blood was with- drawn from the tails of the Acc2 / mutant and wild-type mice after a brief fasting period of 4–5 h, and the serum constituents were determined as described previously (7, 12). Serum levels of glucose, TGs, total cholesterol, high-density lipoprotein cho- lesterol, low-density lipoprotein cholesterol, and very low-den- sity lipoprotein cholesterol were measured by technicians in the Comparative Pathology Laboratory at Baylor College of Medicine. Serum nonesterified fatty acids (NEFAs) were mea- sured by using a NEFA C kit (Wako Chemicals, Richmond, VA). Liver Analyses —All mice were sacrificed after completing their respective dietary regimens, and the livers and epididymal fat pads of the individual animals were weighed. All the livers were surgically sectioned. For each liver, some of the sections were stained with Oil Red O to visualize the TGs as previously described (8); the remaining sections were frozen in liquid nitrogen and kept at 80 °C for further analysis. The tissue concentrations of TGs and cholesterol were measured by using a Cholesterol E Kit (Wako Chemicals) and an Infinity Triglyc-
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  • Winter '19
  • Robert S Kiss
  • The American, Fatty acid metabolism

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