Effect of Ezetimibe on Hepatic Fat, Inflammatory Markers, and Apolipoprotein B-100 Kinetics in Insulin-Resistant Obese Subjects on a Weight Loss Diet

Abstract

OBJECTIVE Nonalcoholic fatty liver disease is highly prevalent in obese and type 2 diabetic individuals and is strongly associated with dyslipidemia and inflammation. Weight loss and/or pharmacotherapy are commonly used to correct these abnormalities. RESEARCH DESIGN AND METHODS We performed a 16-week intervention trial of a hypocaloric, low-fat diet plus 10 mg/day ezetimibe (n = 15) versus a hypocaloric, low-fat diet alone (n = 10) on intrahepatic triglyceride (IHTG) content, plasma high sensitivity–C-reactive protein (hs-CRP), adipocytokines, and fetuin-A concentrations and apolipoprotein (apo)B-100 kinetics in obese subjects. ApoB-100 metabolism was assessed using stable isotope tracer kinetics and compartmental modeling; liver and abdominal fat contents were determined by magnetic resonance techniques. RESULTS Both weight loss and ezetimibe plus weight loss significantly (all P < 0.05) reduced body weight, visceral and subcutaneous adipose tissues, insulin resistance and plasma triglycerides, VLDL–apoB-100, apoC-III, fetuin-A, and retinol-binding protein-4 and increased plasma adiponectin concentrations. Compared with weight loss alone, ezetimibe plus weight loss significantly (all P < 0.05) decreased IHTG content (−18%), plasma hs-CRP (−53%), interleukin-6 (−24%), LDL cholesterol (−18%), campesterol (−59%), and apoB-100 (−14%) levels, with a significant increase in plasma lathosterol concentrations (+43%). The LDL–apoB-100 concentration also significantly fell with ezetimibe plus weight loss (−12%), chiefly owing to an increase in the corresponding fractional catabolic rate (+29%). The VLDL–apoB-100 secretion rate fell with both interventions, with no significant independent effect of ezetimibe. CONCLUSIONS Addition of ezetimibe to a moderate weight loss diet in obese subjects can significantly improve hepatic steatosis, inflammation, and LDL–apoB-100 metabolism.