The Role of Diet1 in Bile Acid Metabolism
Elevated cholesterol levels are associated with increased risk for atherosclerosis, heart disease and stroke. Variations in plasma cholesterol levels among individuals are determined by the interaction of environmental and genetic factors, many of which remain to be identified. This dissertation presents the initial characterization of a novel gene Diet1, the product of which influences plasma cholesterol levels through its effects on bile acid metabolism. Bile acids are synthesized from cholesterol in the liver, and secreted into the small intestine to aid in digestion. At the terminal end of the small intestine, bile acid are actively reabsorbed and sent to the liver (reviewed in Chapter 1).
Preceding my studies, a mutation in Diet1 was identified as the underlying basis for resistance to diet-induced hypercholesterolemia and atherosclerosis in the C57BL/6ByJ inbred mouse strain. My studies have characterized the physiological and cellular function of Diet1, a large modular protein consisting of repeating LDL receptor A2 and MAM (meprin-A5-receptor protein tyrosine phosphatase mu) domains. Diet1 expression is restricted to the small intestine and the kidney cortex. We determined that Diet1 influences the communication from small intestine to liver to modulate the rate at which bile acids are synthesized (Chapter 2). Specifically, Diet1 affects production of the intestinal hormone fibroblast growth factor 15/19 (FGF15/19), which travels through the enterohepatic circulation and activates hepatic receptors, leading to down-regulation of bile acid synthesis. The absence of this regulation in Diet1-deficient mice explains the unregulated conversion of cholesterol to bile acids and protection from hypercholesterolemia that is observed in these animals.
The identification of Diet1 as a determinant of FGF15/19 and bile acid levels in the mouse led to the hypothesis that genetic variation in DIET1 may influence variations in plasma bile acid levels in the human population, and may also underlie disease states characterized by aberrant bile acid levels. To explore these possibilities we resequenced DIET1 in individuals affected with type 2 chronic bile acid diarrhea (Chapter 3), and in individuals from a small Mexican population sample that have extremely high or low bile acid levels (Chapter 4). These studies led to the identification of a common DIET1 nonsynonymous polymorphism that influences the levels of FGF19 secreted from cultured human cells, and an enrichment of rare nonsynonymous DIET1 variants in the individuals with extreme low bile acid levels. Our studies establish Diet1 as a regulator of hepatic bile acid synthesis through its effect on the production of the intestinal hormone FGF15/19. They also implicate genetic variation in DIET1 as a determinant of human FGF19 and bile acid levels.