Abstract 1648: Chromosome 14 Plasma Plant Sterol Locus 14DKK Subcongenic Mice Show Decreased Sterol Absorption and Impaired Bile Acid Metabolism through a Mechanism that May Involve Fibroblast Growth Factor 15 (Fgf15) Signaling
Quantitative trait locus mapping of an intercross between C57BL/6J and castaneus (CASA/Rk) mice revealed a locus on chromosome 14 for plasma plant sterol levels, which was confirmed in congenic and subcongenic strains. The subcongenic strain 14DKK that corresponds to the CASA/Rk chromosome 14 interval from 19.5 to 60 cM on the C57BL/6J background was found to have decreased plasma plant sterol levels and cholesterol absorption. Compared to C57BL/6J mice, 14DKK animals had a 100% increase in fecal bile acids and a 50% decrease in bile acid pool size. In expression studies at the mRNA level, in 14DKK subcongenic ileum Asbt (the ileal bile acid transporter) was decreased 40%, Fgf15 (a secreted protein known to suppress the expression of cholesterol 7-alpha hydroxylase, Cyp7a1, a key enzyme in bile acid synthesis) was increased 25 fold and Fgfr4 (the Fgf15 receptor) increased 2.5 fold. In 14DKK subcongenic liver expression of Cyp7a1 was decreased > 95% and Fgfr4 decreased 20%. We interpret these findings as follows:
In 14DKK subcongenics decreased ileal Asbt expression results in increased fecal loss of bile acids, decreased bile acid pool size, decreased sterol absorption and decreased plasma plant sterol levels.
In these subcongenics the profound decrease in liver Cyp7a1 expression suggests either a primary defect in this gene, which maps out of the 14DKK interval, or a genetic alteration in a factor within the 14DKK interval that regulates its expression.
Massive ileal over expression of Fgf15 may through the Fgfr4 result in autocrine suppression of ileal Asbt, endocrine suppression of liver Cyp7a1 and stimulation of liver bile acid synthesis through a Cyp7a1 independent pathway (which in part makes up for the fecal loss of bile acids). In 14DKK mice a unifying explanation for altered enterohepatic metabolism of sterols and bile acids may be dysregulation of ileal Fgf15 expression.