SREBP-2 expression pattern contributes to susceptibility of Mongolian gerbils to hypercholesterolemia

Abstract

Gerbils are susceptible to dietary cholesterol and prone to hypercholesterolemia and non-alcoholic fatty liver disease. The present study aimed to explore the role of sterol regulatory element binding protein (SREBP)-2 and 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR) in hypercholesterolemia susceptibility in gerbils. Male gerbils were fed the normal diet or a high-fat diet (HFD) for 2 weeks, or the HFD for 2 weeks followed with the normal diet for an additional 2 weeks. Serum lipid levels and hepatic fat deposition were measured, and mRNA and protein levels of SREBP-2 and HMGCR were evaluated by quantitative polymerase chain reaction and Western blotting. In addition, the role of SREBP-2 function in cholesterol synthesis from the gerbil primary hepatic cells was also investigated by modulation of SERBP-2 expression via the transfection of SREBP-2 overexpression and knockdown plasmids, respectively. The data demonstrated that the total cholesterol and low-density lipoprotein cholesterol levels in the gerbil serum samples were rapidly and significantly elevated in response to HFD. In addition, the effect of the HFD was rapidly attenuated in the gerbils following a return to the normal diet. HMGCR expression and activation were not altered by dietary cholesterol consumption in the livers from the gerbils in model or recovery groups. HMGCR expression and activation were effectively regulated in cultured hepatic cells from the gerbils. These results indicated that the activation of SREBP-2 to HMGCR was not terminated in gerbil livers during cholesterol intake. Therefore, stable SREBP-2 expression contributes to the susceptibility of gerbils to hypercholesterolemia.