The Thyromimetic Sobetirome (GC-1) Alters Bile Acid Metabolism in a Mouse Model of Hepatic Cholestasis

Abstract

Chronic cholestasis results from bile secretory defects or impaired bile flow with few effective medical therapies available. Thyroid hormone triiodothyronine and synthetic thyroid hormone receptor agonists, such as sobetirome (GC-1), are known to impact lipid and bile acid (BA) metabolism and induce hepatocyte proliferation downstream of Wnt/β-catenin signaling after surgical resection; however, these drugs have yet to be studied as potential therapeutics for cholestatic liver disease. Herein, GC-1 was administered to ATP binding cassette subfamily B member 4 (Abcb4^-/-; Mdr2^-/-) knockout (KO) mice, a sclerosing cholangitis model. KO mice fed GC-1 diet for 2 and 4 weeks had decreased serum alkaline phosphatase but increased serum transaminases compared with KO alone. KO mice on GC-1 also had higher levels of total liver BA due to alterations in expression of BA detoxification, transport, and synthesis genes, with the net result being retention of BA in the hepatocytes. Interestingly, GC-1 does not induce hepatocyte proliferation or Wnt/β-catenin signaling in KO mice, likely a result of decreased thyroid hormone receptor β expression without Mdr2. Therefore, although GC-1 treatment induces a mild protection against biliary injury in the early stages of treatment, it comes at the expense of hepatocyte injury and is suboptimal because of lower expression of thyroid hormone receptor β. Thus, thyromimetics may have limited therapeutic benefits in treating cholestatic liver disease.