The Niemann-Pick C1 gene is downregulated in livers of C57BL/6J mice by dietary fatty acids, but not dietary cholesterol, through feedback inhibition of the SREBP pathway.

The Niemann-Pick C1 (NPC1) gene is associated with human obesity. Mouse models with decreased Npc1 gene dosage are susceptible to weight gain when fed a high-fat diet, but not a low-fat diet, consistent with an Npc1 gene-diet interaction. The objectives of this study were to define regulation of the Npc1 gene and to investigate the Npc1 gene-diet interaction responsible for weight gain. The experimental design involved feeding C57BL/6J male mice a low-fat diet (with 0.00, 0.10, or 1.00% cholesterol) or a high-fat diet (with 0.02% cholesterol) until 30 wk to determine regulation of the Npc1 gene in liver. The key results showed that the Npc1 gene was downregulated by dietary fatty acids (54%, P = 0.022), but not by dietary cholesterol, through feedback inhibition of the sterol regulatory element-binding protein (SREBP) pathway. However, the dietary fatty acids secondarily increased liver cholesterol, which also inhibits the SREBP pathway. Similarly, the Npc1 gene was downregulated in peritoneal fibroblasts isolated from C57BL/6J weanling male mice not exposed to the experimental diets and incubated in media supplemented with purified oleic acid (37%, P = 0.038) but not in media supplemented with purified cholesterol. These results are important because they suggest a novel mechanism for the interaction of fatty acids with the Npc1 gene to influence energy balance and to promote weight gain. Moreover, the responsiveness of the Npc1 gene to fatty acids is consistent with studies that suggest that the encoded NPC1 protein has a physiologic role in regulating both cholesterol and fatty acid metabolism.