Inhibition of Intestinal Bile Acid Transporter Slc10a2 Improves Triglyceride Metabolism and Normalizes Elevated Plasma Glucose Levels in Mice

Interruption of the enterohepatic circulation of bile acids increases cholesterol catabolism, thereby stimulating hepatic cholesterol synthesis from acetate. We hypothesized that such treatment should lower the hepatic acetate pool which may alter triglyceride and glucose metabolism. We explored this using mice deficient of the ileal sodium-dependent BA transporter (Slc10a2) and ob/ob mice treated with a specific inhibitor of Slc10a2. Plasma TG levels were reduced in Slc10a2-deficient mice, and when challenged with a sucrose-rich diet, they displayed a reduced response in hepatic TG production as observed from the mRNA levels of several key enzymes in fatty acid synthesis. This effect was paralleled by a diminished induction of mature sterol regulatory element-binding protein 1c (Srebp1c). Unexpectedly, the SR-diet induced intestinal fibroblast growth factor (FGF) 15 mRNA and normalized bile acid synthesis in Slc10a2−/− mice. Pharmacologic inhibition of Slc10a2 in diabetic ob/ob mice reduced serum glucose, insulin and TGs, as well as hepatic mRNA levels of Srebp1c and its target genes. These responses are contrary to those reported following treatment of mice with a bile acid binding resin. Moreover, when key metabolic signal transduction pathways in the liver were investigated, those of Mek1/2 - Erk1/2 and Akt were blunted after treatment of ob/ob mice with the Slc10a2 inhibitor. It is concluded that abrogation of Slc10a2 reduces hepatic Srebp1c activity and serum TGs, and in the diabetic ob/ob model it also reduces glucose and insulin levels. Hence, targeting of Slc10a2 may be a promising strategy to treat hypertriglyceridemia and diabetes

IMPORTANCE OF GROWTH-HORMONE FOR THE INDUCTION OF HEPATIC LOW-DENSITY-LIPOPROTEIN RECEPTORS

This investigation was undertaken to determine the possible role of growth hormone (GH) in the hormonal regulation of hepatic low density lipoprotein (LDL) receptor expression. Treatment of normal rats with estrogen (ethynylestradiol, 5 mg/kg per day) increased the number of hepatic LDL receptors, and the LDL receptor mRNA levels were increased 2.4-fold. However, when hypophysectomized rats were treated with estrogen, the hepatic LDL receptor number and the mRNA levels only increased slightly. Treatment with GH was important to restore the induction of hepatic LDL receptors in hypophysectomized estrogen-treated rats. Further, the hypocholesterolemic effect of estrogen was abolished in hypophysectomized rats, and GH reversed this effect. To assess the effect of GH in humans, hepatic LDL receptor binding activity was determined in liver biopsy specimens from gallstone patients pretreated with GH (12 international units/day) prior to operation. GH administration induced hepatic LDL receptors approximately 2-fold, and this was accompanied by a 25% decrease in serum cholesterol. The LDL receptor stimulation caused by GH treatment was of similar magnitude as that observed upon 3 weeks of treatment with an established hypolipidemic drug (pravastatin or simvastatin). The data show that GH has an important role in the regulation of hepatic LDL receptors and suggest that GH secretion may be important for the control of plasma LDL levels in humans