Characterization of Liver-Specific ChREBP Knockout Mice

ChREBP (Carbohydrate Response Element-Binding Protein) and SREBP-1c (Sterol Regulatory Element-Binding Protein-1c) both stimulate the transcription of genes required for lipid synthesis in the liver. My project was designed to investigate the roles of these two factors in regulating the lipogenic pathway. ChREBP and SREBP-1c are induced by carbohydrates, but by different mechanisms. SREBP-1c is stimulated by insulin, while ChREBP is insulin-independent, but dependent on intracellular glucose levels. This issue was studied previously using mice with a germline deletion in ChREBP, but these experiments were limited because these whole-body ChREBP knockout mice did not tolerate a high sucrose diet. To circumvent this problem, we produced mice with a liver-specific knockout of ChREBP (L-ChREBP-/-). When L-ChREBP-/- mice were fasted and refed a high-sucrose diet, they consumed a normal amount of food, but lipogenic gene mRNAs were not induced by refeeding. However, this effect could not be solely attributed to the loss of ChREBP because the L-ChREBP-/- mice unexpectedly also had reduced levels of nuclear SREBP-1. Previous experiments have shown that SREBP-1c is required for the postprandial induction of lipogenic gene mRNAs in the livers of mice subjected to fasting and refeeding. To determine whether the decreased lipogenesis in L-ChREBP-/- mice was caused by reductions in SREBP-1c, ChREBP, or both transcription factors, we injected the L-ChREBP-/- mice with an adeno-associated virus encoding the active nuclear form of SREBP-1c. The expression of some lipogenic genes was restored by normalizing the content of nuclear SREBP-1c, but others were not. Therefore, both SREBP-1c and ChREBP are required for full stimulation of lipogenesis in the postprandial state. Insulin stimulates fatty acid synthesis by activating SREBP-1c. However, glucose is also necessary for lipogenesis, and the additional requirement of ChREBP to induce lipogenic enzymes ensures that the liver will not produce fatty acids unless both insulin and glucose are present.