Premium
G‐protein‐Coupled Bile Acid Receptor Attenuates Liver Injury in a Murine Model of Acute Parenteral Nutrition
Author(s) -
Gomes Charles Klazer,
Rao Prahlad,
Stephenson Erin,
Puchowicz Michelle,
Makowski Liza,
Han Joan K.,
Yin Dengping,
Chang Eugene B.,
Pierre Joseph F.
Publication year - 2018
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.2018.32.1_supplement.759.6
Subject(s) - g protein coupled bile acid receptor , bile acid , deoxycholic acid , medicine , cholesterol 7 alpha hydroxylase , taurocholic acid , steatosis , endocrinology , enterohepatic circulation , chenodeoxycholic acid , cyp8b1 , biology
Parenteral Nutrition (PN) provides essential caloric support in patients unable to feed enterally. Unfortunately, PN without enteral feeding is associated with hepatic injury, especially in neonates where PN associated liver disease (PNALD) affects 60–70% of recipients. PN alters intestinal physiology and host‐microbial interactions, including bile acid enterohepatic circulation, which regulates metabolism through nuclear and cell membrane bile acid receptors. Here, we examined the role of G‐protein coupled bile acid receptor deficiency (TGR5 −/− ) upon hepatic phenotype in a murine model of acute PN. TGR5 −/− and wild type (WT) received PN for 96 hours. PN significantly elevated serum triglycerides, resistin, PAI‐1 and hepatic fatty acid synthesis gene expression in both genotypes. However, PN‐treated TGR5 −/− animals had significantly larger liver weights compared with WT, but displayed no changes in triglycerides. Histological analysis instead suggested edema. Accordingly, TGR5 −/− animals on PN displayed elevated hepatic IL‐6 expression and significantly higher serum AST and ALT levels compared with WT. Furthermore, TGR5 −/− animals on PN also displayed significantly decreased bile acid synthesis genes, including Cyp7A1, Cyp8B1, Cyp7B1, and BAT, compared with WT. Therefore, we examined serum bile acid composition. PN elevated total conjugated primary bile acid levels, specifically TCA, TCDCA, TbMCA, and TaMCA, in both genotypes compared with chow. However, TGR5 −/− on PN displayed markedly higher levels of the unconjugated primary bile acids, CDCA, aMCA, and the secondary bile acids, oMCA and DCA, compared with WT on PN. Predictive metagenomics of 16S sequencing suggested altered microbial enzymes in TGR5 − / − , including BSH and 7alpha hydroxylase, consistent with serum bile acid changes. These results suggest a protective role for TGR5 in liver function during PN that potentially includes direct attenuation of hepatic inflammation or indirect manipulation through microbiota‐bile acid interactions. Greater mechanistic understanding of TGR5 signaling during PN might improve interventions to treat or prevent PNALD. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .