Regulation of Synthesis

The rate-limiting enzyme in cholesterol biosynthesis is 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, a microsomal enzyme that converts

HMG-CoA to mevalonic acid in the polyisoprenoid synthetic pathway. Peripheral tissue cholesterol synthesis is much less responsive to regulatory factors compared to the liver, which is controlled by a variety of dietary, hormonal, and physiological variables. Studies indicate that endogenous cholesterol synthesis is significantly increased in obesity and in patients with the metabolic syndrome. Obesity, insulin resistance, and diabetes have pronounced effects on both cholesterol absorption and synthesis. Findings in type 1 diabetes appear to be related to low expression of ABCG5/G8 genes, resulting in high absorption and low synthesis of cholesterol. Cholesterol absorption efficiency is lower and cholesterol synthesis is higher in obese subjects with type 2 diabetes compared to obese subjects without diabetes, suggesting that diabetes modulates cholesterol metabolism to a greater extent than obesity alone. Similarly, low cholesterol absorption and high synthesis appear to be part of the insulin resistance (metabolic) syndrome.

Research shows that in most individuals, dietary cholesterol alters endogenous cholesterol synthesis and that this feedback regulation can effectively compensate for increased cholesterol input from dietary sources. The precision of these regulatory responses depends on a number of genetic factors, and data suggest that multiple genetic loci are involved. For example, family studies have shown that in siblings of low cholesterol absorption families, cholesterol absorption percentages are significantly lower and cholesterol and bile acid synthesis, cholesterol turnover, and fecal steroids are significantly higher than in siblings of high absorption families.

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