The Niemann‐Pick C1 gene interacts with a high‐fat diet and modifying genes to promote weight gain

The Niemann-Pick C1 gene in both humans (NPC1) and mice (Npc1) is localized to chromosome 18 and encodes a large complex membrane-boundproteinwith extensive structural homologywith members of the resistance-nodulation-division (RND) family of prokaryotic permeases [Davies et al., 2000; Davies and Ioannou, 2000]. Although exact function of the NPC1 protein remains undefined, studies indicate that this protein has a central role in regulating the transport of cholesterol and fatty acids from late endosomes/lysosomes to other cellular compartments and therefore maintaining cellular, tissue, and whole body lipid homeostasis [Xie et al., 1999;Chen et al., 2005]. Since themid 1980 sec, theNPC1 gene has been investigated only in relation to a rare autosomalrecessive lipid-storage disorder characterized by clinical manifestations involving the liver and brain [Garver et al., 2007]. However, a recent genome-wide association study has revealed that theNPC1 gene is also associated with common childhood and adult obesity, a disparate metabolic disease that has now reached epidemic proportions worldwide [Meyre et al., 2009]. Consistent with this report, subsequent studies performed using BALB/cJ and hybrid BALB/cJ-C57BL/6J Npc1 mouse models found that Npc1 gene haploinsufficiency promotes weight gain, therefore validating the NPC1 gene as a legitimate candidate responsible for common human obesity [Jelinek et al., 2010a,b]. The present research letter provides evidence indicating that theNpc1 gene interacts with both a high-fat diet and modifying genes to promote weight gain, consistent with common human obesity being a complex multifactorial disease. A breeding pair of BALB/cJ Npc1 heterozygous (Npc1þ/ ) mice and C57BL/6JNpc1 normal (Npc1þ/þ) mice was obtained from the Jackson Laboratory (Bar Harbor, ME). These mice were bred to generate pure BALB/cJ Npc1þ/þ and Npc1þ/ mice and hybrid BALB/cJ-C57BL/6J Npc1þ/þ and Npc1þ/ mice as previously described [Jelinek et al., 2010a,b]. The Npc1 genotype was determined at the time of weaning (21 days) using a polymerase chain reaction [Loftus et al., 1997]. One week after weaning, the male Npc1þ/þ and Npc1þ/ mice were placed on either a low-fat diet (10–14% kcal from fat) or high-fat diet (45% kcal from fat), maintained and fed (ad libitum), and weighed at 10 weeks of age. The mice were initially produced and maintained at the University of Arizona Animal Care Facility and subsequently at the University of New Mexico Health Sciences Center Animal Resources Facility in accordance to the Institutional Animal Care and Use Committee. The results showed no significant difference in the body weights of BALB/cJNpc1þ/þ andNpc1þ/ mice fed a low-fat diet. However, when these BALB/cJ mice were fed a high-fat diet, Npc1þ/ mice had significantly increased (8.8%) body weights compared to Npc1þ/þ mice at 10 weeks of age, indicating an Npc1 gene–diet interaction in relation to weight gain (Fig. 1A). Similarly, when BALB/cJ-C57BL/6JNpc1þ/þ andNpc1þ/ mice were fed a high-fat diet, Npc1þ/ mice had significantly increased (37.4%) body weights compared to Npc1þ/þ mice at 10 weeks of age, again indicating an Npc1 gene–diet interaction in relation to weight gain (Fig. 1B). However, unlike BALB/cJ Npc1þ/ mice fed a low-fat diet, BALB/cJ-C57BL/6J Npc1þ/ mice fed a low-fat diet also had significantly increased (16.1%) body weights compared to BALB/cJ-C57BL/6J Npc1þ/þ mice at 10 weeks of age, therefore indicating an Npc1 gene–modifying gene interaction in relation to weight gain. Together, BALB/cJ-C57BL/6J Npc1þ/ mice fed a high-fat diet had significantly increased (51%) body weights compared to BALB/cJ-C57BL/6J Npc1þ/þ mice fed a low-fat