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

Abstract

Background & Aims 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. Methods 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. Results 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. Conclusions Pharmacologically targeting hepatic bile acid uptake to increase bile acid signaling is a novel approach to treat obesity and induce GLP1- secretion.

A New Treatment for Chronic Hepatitis B and D Offers Novel Insights Into Obesity and Hepatic Steatosis

“…It has been shown to be safe and well-tolerated 17,18 and is currently in phase 2b and phase 3 clinical trials for treatment of HBV and HDV infections, respectively. Because myrcludex B inhibits hepatic bile uptake, it might be potentially used to treat metabolic diseases, which is supported by the current study of Donkers et al 13 These novel data demonstrate that NTCP inhibition decreases hepatic bile acid clearance and induces glucagon-like peptide 1 (GLP-1) mediated thermogenesis in brown adipose tissue, stimulates fatty acid oxidation, and increases fecal energy excretion, leading to a reduction in body weight and hepatic steatosis. At the same time, thyroid hormone activation and energy expenditure were not affected by myrcludex B.…”

“…At the same time, thyroid hormone activation and energy expenditure were not affected by myrcludex B. 13 GLP-1 analogues themselves have been already identified as potential targets to treat obesity and NAFLD because they decrease body weight and improve histologic features of NAFLD and NASH 19 and also reduce the risk of cardiovascular diseases. 20 However, NTCP inhibition might be superior to GLP-1 agonists by using and prolonging the natural meal-dependent bile acid dynamics.…”

“…Currently, bariatric surgery is the most effective measure to reduce body weight and seems to be effective on metabolic state and NAFLD, including inflammation and fibrosis, 12 although bariatric surgery is an invasive intervention with corresponding risks. Donkers et al 13,14 open another promising path for obese patients. Previous and current works describe a novel mechanism using the physiological situation of bile increase and extend circulation time.…”

“…Donkers et al 13 , 14 open another promising path for obese patients. Previous and current works describe a novel mechanism using the physiological situation of bile increase and extend circulation time.…”

Targeting the Four Pillars of Enterohepatic Bile Salt Cycling; Lessons From Genetics and Pharmacology

“…Preclinical studies in mice offer promise for additional applications of NTCP inhibitors in conditions of hypercholesterolemia, obesity and cholestasis. (50)(51)(52) NtCp-DeFICIeNt MICe NTCP-deficient mice, first described by Slijepcevic et al, (53) showed that some redundancy exists in hepatocytic uptake systems for bile salts in mice, due to the expression of other transporters of the organic anion transporting polypeptide (OATP) 1a/1b family. Most mice displayed no elevated bile salt levels at all, whereas a subset of these KO mice exhibited strong hypercholanemia.…”