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  • Inhibition of Hepatic Bile Acid Uptake by Myrcludex B Promotes Glucagon-Like Peptide-1 Release and Reduces Obesity.

Inhibition of Hepatic Bile Acid Uptake by Myrcludex B Promotes Glucagon-Like Peptide-1 Release and Reduces Obesity.

Cellular and molecular gastroenterology and hepatology (2020-04-25)
Joanne M Donkers, Reinout L P Roscam Abbing, Michel van Weeghel, Johannes H M Levels, Anita Boelen, Alfred H Schinkel, Ronald P J Oude Elferink, Stan F J van de Graaf
ABSTRACT

Bile acids are important metabolic signaling molecules. Bile acid receptor activation promotes body weight loss and improves glycemic control. The incretin hormone GLP-1 and thyroid hormone activation of T4 to T3 have been suggested as important contributors. Here, we identify the hepatic bile acid uptake transporter Na+ taurocholate co-transporting polypeptide (NTCP) as target to prolong postprandial bile acid signaling. Organic anion transporting polypeptide (OATP)1a/1b KO mice with or without reconstitution with human OATP1B1 in the liver were treated with the NTCP inhibitor Myrcludex B for 3.5 weeks after the onset of obesity induced by high fat diet-feeding. Furthermore, radiolabeled T4 was injected to determine the role of NTCP and OATPs in thyroid hormone clearance from plasma. Inhibition of NTCP by Myrcludex B in obese Oatp1a/1b KO mice inhibited hepatic clearance of bile acids from portal and systemic blood, stimulated GLP-1 secretion, reduced body weight, and decreased (hepatic) adiposity. NTCP inhibition did not affect hepatic T4 uptake nor lead to increased thyroid hormone activation. Myrcludex B treatment increased fecal energy output, explaining body weight reductions amongst unaltered food intake and energy expenditure. Pharmacologically targeting hepatic bile acid uptake to increase bile acid signaling is a novel approach to treat obesity and induce GLP1- secretion.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Eosin Y disodium salt, certified by the Biological Stain Commission
Sigma-Aldrich
Hematoxylin solution according to Mayer
Sigma-Aldrich
GW4064, ≥97% (HPLC)
Millipore
Glucagon Like Peptide-1 (Active) ELISA, This Glucagon Like Peptide-1 (Active) ELISA is used to measure & quantify Glucagon Like Peptide-1 levels in Metabolism & Endocrine research.
Sigma-Aldrich
Adenosine 3′,5′-cyclic monophosphate tris salt, ≥97% (HPLC), powder