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Treatment of a Mouse Model of Cholestasis with a Thyromimetic Improves Biliary Injury But Exacerbates Hepatocyte Injury
Author(s) -
Kosar Karis P,
NejakBowen Kari
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.126.7
Subject(s) - cholestasis , medicine , endocrinology , liver injury , hepatocyte , bile acid , bilirubin , alkaline phosphatase , biology , fibrosis , chemistry , enzyme , biochemistry , in vitro
Chronic cholestasis results from bile secretory defects or impairment of bile flow, and there are few effective medical therapies available. Thyroid hormone T3 and synthetic thyroid hormone receptor agonists are known to cause induction of hepatocyte proliferation during liver regeneration. However, whether these drugs have therapeutic benefits in cholestatic liver disease is unknown. In this study, we administered GC‐1, a thyromimetic that preferentially acts through the TRb receptor found predominantly in liver, to Mdr2 knockout (KO) mice, which is a commonly used model of sclerosing cholangitis characterized by bile acid (BA) regurgitation, periductular inflammation, and fibrosis. We determined Mdr2 KO mice fed 5mg/kg GC‐1 diet had decreased bilirubin, liver to body weight ratios, serum alkaline phosphatase, but increased serum alanine aminotransferase and aspartate aminotransferase compared to KO mice fed normal diet as early as 1 week on diet. Histologically, KO mice on GC‐1 diet had decreased ductular response, less bridging fibrosis, and fewer SOX9 positive hepatocytes compared to KO on normal diet. Although total liver BA were higher in KO mice fed GC‐1 diet for 2 weeks compared to normal diet, they normalized to KO levels at 4 weeks of diet. To elucidate the mechanism of increased BA accumulation and liver injury, we examined expression of BA transporters and detoxification enzymes. KO mice on GC‐1 diet had decreased bilirubin transport and detoxification genes, such as Mrp3, Cyp2b10, and Oatp4, compared to KO mice on normal diet, with the net result being retention of BA in the hepatocyte. Affymetrix gene array data also indicates that KO mice on GC‐1 have normalized bile acid synthesis compared to WT expression levels. Thus, GC‐1 reduces cholangiocyte injury during cholestasis by inducing retention of BA in hepatocytes, causing injury to the hepatocytes; this occurs through as‐yet unknown mechanisms that are upstream of BA transporters and biosynthesis enzymes and appears to be b‐catenin independent. Support or Funding Information National Institute of Biomedical Imaging and Bioengineering of the National Institute of Health under Award Number T32EB0010216UPP Academic Foundation Award 1R01DK103775 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .