Bile Salt Sequestration Induces Hepatic De Novo Lipogenesis Through Farnesoid X Receptor– and Liver X Receptorα–Controlled Metabolic Pathways in Mice

Abstract

Diabetes is characterized by high blood glucose levels and dyslipidemia. Bile salt sequestration has been found to improve both plasma glycemic control and cholesterol profiles in diabetic patients. Yet bile salt sequestration is also known to affect triglyceride (TG) metabolism, possibly through signaling pathways involving farnesoid X receptor (FXR) and liver X receptor ␣ (LXR␣). We quantitatively assessed kinetic parameters of bile salt metabolism in lean C57Bl/6J and in obese, diabetic db/db mice upon bile salt sequestration using colesevelam HCl (2% wt/wt in diet) and related these to quantitative changes in hepatic lipid metabolism. As expected, bile salt sequestration reduced intestinal bile salt reabsorption. Importantly, bile salt pool size and biliary bile salt secretion remained unchanged upon sequestrant treatment due to compensation by de novo bile salt synthesis in both models. Nevertheless, lean and db/db mice showed increased, mainly periportally confined, hepatic TG contents, increased expression of lipogenic genes, and increased fractional contributions of newly synthesized fatty acids. D iabetes is a multifactorial disease characterized by increased fasting blood glucose levels and dyslipidemia-that is, high plasma triglyceride (TG) and low-density lipoprotein cholesterol levels. Controlling blood glucose and cholesterol levels in diabetic patients is critical for delaying the progression of clinical complications such as neuropathy and cardiovascular disease. An efficient way to reduce plasma cholesterol levels is to induce cholesterol secretion in bile, either as bile salt or as free cholesterol. Bile is secreted into the ileum to facilitate absorption of lipids and lipid-soluble vitamins. About 95% of secreted bile salts are reabsorbed in the terminal ileum and transported back to the liver through the portal vein (enterohepatic circulation). In addition to their function in the absorption of dietary fats, bile salts are signaling molecules that play an important role in the regulation of lipid metabolism. 1 Interestingly, bile salt metabolism is affected in diabetes, which might contribute to the altered lipid profile observed in diabetic patients. 2 Knowledge of potential disturbances in bile salt metabolism in type 2 diabetic humans and animal models is still very limited, however. 3 Increasing fecal bile salt loss by preventing their intestinal reabsorption (sequestration) increases bile salt synthesis and, hence, hepatic cholesterol turnover. As a consequence, low-density lipoprotein cholesterol levels

Effect of bile acid sequestrants on glucose metabolism, hepatic de novo lipogenesis, and cholesterol and bile acid kinetics in type 2 diabetes: a randomised controlled study

“…Studies in healthy participants have suggested that BA synthesis is regulated in part by FGF-19 [12,48], but a similar relationship in type 2 diabetes was not seen in a previous study [12]. FGF-19 has been shown to inhibit fatty acid synthesis in cultured hepatocytes [49] and bile acid sequestration in diabetic db/db mice resulted in an increase in DNL [3]. We did not, however, see an increase in DNL with colesevelam treatment in patients with type 2 diabetes.…”

“…These agents form non-absorbable complexes with bile acids, which inhibits their reabsorption in the ileum [2] and increases faecal excretion. In response, the nuclear receptor farnesoid X receptor (FXR)-mediated inhibition of cholesterol 7α-hydroxylase is reduced in the liver and bile acid synthesis from cholesterol is upregulated [3] and the expression of LDL receptors is upregulated and the clearance of LDLcholesterol from the blood is increased. BAS have also been shown to improve glycaemic control in individuals with type 2 diabetes mellitus [4].…”

Hepatic glucose sensing is required to preserve β cell glucose competence

“…For instance, treatment with colesevelam improves glucose homeostasis in diabetic mice, but this occurs without changing the total BA pool (36,37). There is also evidence that improvement of glucose homeostasis upon sequestrant treatment is mediated by increased GLP-1 secretion induced by the ingested fat that is not absorbed when intestinal BAs are reduced (38).…”

Bile acid receptors as targets for the treatment of dyslipidemia and cardiovascular disease

“…However, TGR5 modulators are expected to be useful for the treatment of T2D, and an emerging function of TGR5 in monocytes and macrophages ( 133 ) might open up therapeutic options to target the infl ammatory component of CVD and T2D. inhibition of lipogenesis increases hepatic steatosis at least in rodents ( 150 ). Administration of colestimide for 24 weeks lowers ALT and aspartate aminotransferase (AST), but not GGT in NASH patients.…”