FIGURE 10.

Schematic proposed model for major metabolic pathways affected by ACC2 deletion in the livers of wild-type mice fed FFHC and HFHC diets. Master regulators of fat metabolic enzymes (SREBP1, SREBP2, ChREBP, and PPAR-γ) are induced under FFHC feeding conditions that result in up-regulation of key enzymes in fatty acid and cholesterol metabolism (ACL, ACC1, ACC2, FAS, mevalonate pyrophosphate decarboxylase (MVD), and 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGR)). In livers of wild-type mice, where ACC2 is highly active, the malonyl-CoA produced blocks the activity of CPT1, thus inhibiting fatty acid oxidation and leading to excessive accumulation of excessive TGs and more fat (A). When ACC2 is deleted, there is a further increase in the transcriptional factors of fat synthesis, resulting in even more up-regulation of the lipogenic enzymes. However, the lack of CPT1 inhibition by ACC2-produced malonyl-CoA results in increased fatty acid oxidation and significant reduction in the accumulation of long-chain fatty acids and TGs and prevents fatty liver (B). Under HFHC feeding conditions, the livers of wild-type mice accumulate high levels of TGs as a result of exogenous fatty acids and de novo synthesis from the high carbohydrate in the diet (C). In livers of ACC2 mutant mice, fewer TGs accumulate due both to down-regulation of lipogenic enzymes and increased fatty acid oxidation, thus preventing excessive accumulation of TGs in these livers (D). The decrease in acylglycerides in livers of Acc2^−/− mutant mice on a HFHC diet will result in an increase in pAKT that will enhance insulin sensitivity and increase glucose uptake (D). Thick arrows indicate up-regulation.