Cholesterol exacerbates diet-induced obesity, insulin resistance, and dyslipidemia, via induction of hepatic lipogenesis and steatosis.

Although the atherogenic role of dietary cholesterol has been wellestablished, its diabetogenic potential and associated metabolic disturbances have not been reported. Diet-induced hamster models of insulin resistance and dyslipidemia were employed to determine lipogenic and diabetogenic effects of dietary cholesterol. Metabolic studies were conducted in hamsters fed diets rich in fructose (40%), fat (30%), and cholesterol (0.05–0.25%) (FFC) and other test diets. Short-term feeding of the FFC diet induced insulin resistance, glucose intolerance,  hypertriglyceridemia, and hypercholesterolemia. Prolongedfeeding (6–22 wk) of the FFC diet led to severe hepatic steatosis, glucose intolerance, and mild increases in fasting blood glucose, suggesting progression toward type 2 diabetes, but did notinduce β-cell dysfunction. Metabolic changes induced by the diet,including dyslipidemia and insulin resistance, were cholesterol concentration dependent and were only markedly induced on a highfructose and high-fat dietary background. There were significant increases in hepatic and plasma triglyceride with FFC feeding, likely due to a 10- to 15-fold induction of hepatic stearoyl-CoA desaturase compared with chow levels (P < 0.03). Hepatic insulin resistance was evident based on reduced tyrosine phosphorylation of the insulin receptor-β, IRS-1, and IRS-2 as well as increased protein mass of protein tyrosine phosphatase 1B. Interestingly, nuclear liver X receptor (LXR) target genes such as ABCA1 were upregulated on the FFC diet, and dietary supplementation with an LXR agonist (instead of dietary cholesterol) worsened dyslipidemia, glucose intolerance, andupregulation of target mRNA and proteins similar to that of dietarycholesterol. In summary, these data clearly implicate dietary cholesterol, synergistically acting with dietary fat and fructose, as a major determinant of the severity of metabolic disturbances in the hamster model. Dietary cholesterol appears to induce hepatic cholesterol ester and triglyceride accumulation, and diet-induced LXR activation (via cholesterol-derived oxysterols) may possibly be one key underlying mechanism.