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

Abstract

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.

Inhibition of ileal apical but not basolateral bile acid transport reduces atherosclerosis in apoE−/− mice

“…As previously demonstrated in Asbt −/− mice [11, 12], hepatic expression of Cyp7a1, sterol 12α-hydroxylase (Cyp8b1), HMG CoA reductase (Hmgcr), and HMG CoA synthase (Hmgcs) were elevated in Asbt −/− apoE −/− versus apoE −/− mice (Fig. 3A).…”

“…The effects associated with Asbt-deficiency in apoE −/− or Ldlr −/− mice were similar to those reported for bile acid sequestrants [18], ASBT inhibitors [20–22], or ASBT mutations in humans [23] and mice [11, 12], and included decreased levels of plasma apoB containing lipoproteins and decreased aortic cholesterol deposition. The Asbt −/− apoE −/− mice exhibited increased hepatic cholesterol demand for bile acid synthesis, as evidenced by the reduced hepatic total cholesterol content and increased expression of HMG-CoA reductase, HMG-CoA synthase, Cyp7a1, and Cyp8b1.…”

“…Inactivation of either Asbt or Ostα impairs intestinal bile acid transport. However, Ostα null mice fail to induce hepatic expression of cholesterol 7α-hydroxylase (Cyp7a1) and bile acid synthesis [9, 10], in striking contrast to a block in ileal apical brush border membrane uptake of bile acids [11, 12]. This is thought to be due to an inability to down-regulate expression of the ileal-derived polypeptide hormone fibroblast growth factor (FGF) 15 (human ortholog: FGF19) in Ostα −/− mice [13].…”

Fibroblast Growth Factor Receptor 4 (FGFR4) Deficiency Improves Insulin Resistance and Glucose Metabolism under Diet-induced Obesity Conditions

“…Reportedly, FGFR4 KO mice exhibit worsened glucose disposal and increased adipose depot size. Because FGFR4 KO mice had increased bile acid synthesis, the worsening effect on glucose metabolism appears inconsistent with effects of bile acids to prevent hyperglycaemia and insulin resistance (19) and the beneficial effects on glucose metabolism in other situations of increased bile acid synthesis, such as from bile acid resin treatment (20) or in mice with defective intestinal bile acid transporter (21). Additionally, a recent study of liver-specific FGFR4 knockdown mice, using an antisense RNA approach, resulted in improvement in glucose metabolism, insulin sensitivity, and reduction in body weight (22).…”

Bile Acid Uptake Transporters as Targets for Therapy

“…Preclinical studies further showed that ASBT-inhibition reduces hepatic triglyceride and cholesterol accumulation in high fat diet-fed mice [61,62]. Similarly, bile acid-binding resins, including cholestyramine and colesevelam, have been shown to reduce serum total sterols including LDL-cholesterol values.…”