Circulating lipoproteins and hepatic sterol metabolism in Psammomys obesusprone to obesity, hyperglycemia and hyperinsulinemia

The liver plays a central role in lipoprotein metabolism and cholesterol ho meostasis. As the physiopathology of lipid disorders in non-insulin-depende nt diabetes mellitus (NIDDM) is multifactorial and still imperfectly known, we evaluated its onset on plasma lipid transport and hepatic cholesterol m etabolism in Psammomys obesus. This sand rat lapses into hyperinsulinemia a nd hyperglycemia when transferred from its native food to laboratory rodent diets. Marked hypertriglyceridemia and hypercholesterolemia developed in h yperinsulinemic (Group B) and hyperglycemic/hyperinsulinemic (Group C), com pared with normal P. obesus (Group A). Group B showed significantly (P <0.0 5) higher plasma VLDL-cholesterol (41.9%) and LDL-cholesterol (47.3%) conce ntrations, whereas Group C was characterized by an even more marked increas e in VLDL-cholesterol (176%. P < 0.001) compared with Group A. Lipoprotein composition was also altered, displaying impaired lipid and apolipoprotein moiety distribution in IDL, LDL, HDL2 and HDL3 lipoprotein fractions of Gro ups B and C. The activity of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme in cholesterol biosynthesis, was consis tently lower in Group B (P<63.4%, P<0.001) and C (43.9%, P < 0.005). In con trast, the direct measurement of microsomal acyl-CoA:cholesterol acyltransf erase (ACAT), controlling the acylation of cholesterol, showed an increase averaging 53% in Group B (P < 0.01) and 61% in Group C (P < 0.005). Similar ly, elevted activity (171.1%, P < .05 and 291.4%, P < 0.001, respectively) was related to cholesterol 7<alpha>-hydroxylase, the rate-limiting enzyme i n bile acid biosynthesis. These alterations were accompanied with abundant deposition of triglycerides and cholesterol in the liver. Changes in circul ating lipids and liver parameters were related to glucose and insulin level s, indicating the implication of insulin resistance and diabetes. Therefore , our findings demonstrate various disturbances in plasma lipid profile and lipoprotein composition, as well as in liver cholesterol metabolism during the sequential development of insulin resistance and diabetes in P. obesus rats. Furthermore, the current data point to an undoubtedly important role of the liver in the pathogenesis of metabolic disorders in the progression of nutritionally-induced insulin resistance and diabetes in P. obesus. Fin ally, current research shows that more marked plasma and hepatic lipid pert urbations occur in insulin resistance than in diabetes, which may culminate in the development of atherosclerosis. (C) 2001 Elsevier Science Ireland L td. All rights reserved.