Bile acid sequestrants (BASs) are
cholesterol-lowering drugs that also affect
hyperglycemia. The mechanism by which BASs exert these and other metabolic effects beyond
cholesterol lowering remains poorly understood. The present study aimed to investigate the effects of a BAS,
colestilan, on
body weight, energy expenditure, and
glucose and lipid metabolism and its mechanisms of action in high-fat-fed hyperlipidemic
APOE*3 Leiden (E3L) transgenic mice. Mildly
insulin-resistant E3L mice were fed a high-fat diet with or without 1.5%
colestilan for 8 weeks.
Colestilan treatment decreased
body weight, visceral and subcutaneous fat, and plasma
cholesterol and
triglyceride levels but increased food intake.
Blood glucose and plasma
insulin levels were decreased, and hyperinsulinemic-euglycemic clamp analysis demonstrated improved
insulin sensitivity, particularly in peripheral tissues. In addition,
colestilan decreased energy expenditure and physical activity, whereas it increased the respiratory exchange ratio, indicating that
colestilan induced
carbohydrate catabolism. Moreover, kinetic analysis revealed that
colestilan increased [(3)H]
NEFA incorporation in biliary
cholesterol and
phospholipids and increased fecal
lipid excretion. Gene expression analysis in liver, fat, and muscle supported the above findings. In summary,
colestilan decreases
weight gain and improves peripheral
insulin sensitivity in high-fat-fed E3L mice by enhanced
NEFA incorporation in biliary
lipids and increased fecal
lipid excretion.