The human Niemann-Pick C1 (NPC1) gene has been found to be associated with extreme (early-onset and morbid-adult) obesity and type 2 diabetes independent of body weight. We previously performed growth studies using BALB/cJ Npc1 normal (Npc1+/+) and Npc1 heterozygous (Npc1+/-) mice and determined that decreased Npc1 gene dosage interacts with a high-fat diet to promote weight gain and adiposity. The present study was performed using both BALB/cJ and C57BL/6J Npc1+/+ and Npc1+/- mice to determine if decreased Npc1 gene dosage predisposes to metabolic features associated with type 2 diabetes. The results indicated that C57BL/6J Npc1+/- mice, but not BALB/cJ Npc1+/- mice, have impaired glucose tolerance when fed a low-fat diet and independent of body weight. The results also suggest that an accumulation of liver free fatty acids and hepatic lipotoxicity marked by an elevation in the amount of plasma alanine aminotransferase (ALT) may be responsible for hepatic insulin resistance and impaired glucose tolerance. Finally, the peroxisome-proliferator activated receptor α (PPARα) and sterol regulatory element-binding protein-1 (SREBP-1) pathways known to have a central role in regulating free fatty acid metabolism were downregulated in the livers, but not in the adipose or muscle, of C57BL/6J Npc1+/- mice compared to C57BL/6J Npc1+/+ mice. Therefore, decreased Npc1 gene dosage among two different mouse strains interacts with undefined modifying genes to manifest disparate yet often related metabolic diseases.
Keywords: ALT; AST; Adiposity; Cholesterol; Free fatty acids; GWAS; HOMA-IR; HOMA-β%; INSIG; IPGTT; IPITT; LXRα; NPC1; Niemann–Pick C1; Obesity; PCR; PPARα; QUICKIE; SCAP; SNP; SREBP; SREBP cleavage activating protein; Type 2 diabetes; alanine aminotransferase; aspartate aminotransferase; genome-wide association study; homeostasis model assessment-insulin resistance index; homeostasis model assessment-β cell function percentile; insulin-induced gene; intraperitoneal glucose tolerance test; intraperitoneal insulin tolerance test; liver X receptor α; peroxisome-proliferator activated receptor α; polymerase chain reaction; quantitative insulin sensitivity check index; single nucleotide polymorphism; sterol regulatory element-binding protein.
Published by Elsevier B.V.