The intestine as a regulator of cholesterol homeostasis in diabetes

The chylomicron influences very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) composition but itself is atherogenic. Thus abnormalities of chylomicron production are of interest particularly in conditions such as diabetes which confer major cardiovascular risk. Intestinal function is abnormal in diabetes and is a major cause of the dyslipidaemia found in this condition. Studies have suggested that cholesterol absorption is decreased in diabetes and cholesterol synthesis increased. Molecular mechanisms involved in insulin resistance in the intestine and its effect on cholesterol homeostasis in diabetes are described. Abnormalities in triglyceride synthesis and alterations genes regulating cholesterol absorption and intestinal synthesis are discussed. In particular, increase in apolipoprotein B48 synthesis has been demonstrated in animal models of diabetes and insulin resistance. Intestinal mRNA expression of Niemann Pick C1-like 1, protein is increased in both experimental and human diabetes suggesting that an increase in cholesterol transportation does occur. mRNA expression of the ATP binding cassette proteins (ABC) G5 and G8, two proteins working in tandem to excrete cholesterol have been shown to be decreased suggesting increased delivery of cholesterol for absorption. Expression of microsomal triglyceride transfer protein, which assembles the chylomicron particle, is increased in diabetes leading to increase in both number and cholesterol content. In conclusion, diabetes is associated with considerable dysfunction of the intestine leading to abnormal chylomicron composition which may play a major part in the premature development of atherosclerosis.