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.
Karolinska Institute, Department of Endocrinology, Metabolism and Diabetes, and Molecular Nutrition Unit, Center for Biosciences, NOVUM, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Thomas
T
Lundåsen
Eva-Marie
EM
Andersson
Michael
M
Snaith
Helena
H
Lindmark
Johanna
J
Lundberg
Ann-Margret
AM
Östlund-Lindqvist
Bo
B
Angelin
Mats
M
Rudling
D000222:Adaptation, Physiological; D000818:Animals; D001647:Bile Acids and Salts / Q000172:deficiency / Q000378:metabolism; D001786:Blood Glucose; D002784:Cholesterol / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism; D004032:Diet; D005227:Fatty Acids / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D029363:Organic Anion Transporters, Sodium-Dependent / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D027981:Symporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000097:blood / Q000378:metabolism*
D001647:Bile Acids and Salts; D001786:Blood Glucose; D005227:Fatty Acids; D029363:Organic Anion Transporters, Sodium-Dependent; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D027981:Symporters; D014280:Triglycerides; C414620:fibroblast growth factor 21; C071908:sodium-bile acid cotransporter; D005346:Fibroblast Growth Factors; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase; C502772:Cyp7a1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2