Ezetimibe increases intestinal expression of the LDL receptor gene in dyslipidaemic men with insulin resistance.

AIM: To gain further insight into intestinal cholesterol homeostasis in dyslipidaemic men with insulin resistance (IR) by examining the impact of treatment with ezetimibe on the expression of key genes involved in cholesterol synthesis and LDL receptor (R)-mediated uptake of lipoproteins.

METHODS: A total of 25 men with dyslipidaemia and IR were recruited to participate in this double-blind, randomized, crossover, placebo-controlled trial. Participants received 10 mg/day ezetimibe or placebo for periods of 12 weeks each. Intestinal gene expression was measured by quantitative PCR in duodenal biopsy samples collected by gastroduodenoscopy at the end of each treatment.

RESULTS: A total of 20 participants completed the protocol. Treatment with ezetimibe significantly increased intestinal LDLR (+16.2%; P = .01), 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoAR; +14.0%; P = .04) and acetyl-Coenzyme A acetyltransferase 2 (ACAT-2) mRNA expression (+12.5%; P = .03). Changes in sterol regulatory element-binding transcription factor 2 (SREBP-2) expression were significantly correlated with changes in HMG-CoAR (r = 0.55; P < .05), ACAT-2 (r = 0.69; P < .001) and proprotein convertase substilisin/kexin type 9 (PCSK9) expression (r = 0.45; P < .05).

CONCLUSIONS: These results show that inhibition of intestinal cholesterol absorption by ezetimibe increases expression of the LDLR gene, supporting the concept that increased LDL clearance with ezetimibe treatment occurs not only in the liver but also in the small intestine.