Language
English
Publication Date
12-1-2023
Journal
Journal of Lipid Research
DOI
10.1016/j.jlr.2023.100469
PMID
37922990
PMCID
PMC10698000
PubMedCentral® Posted Date
11-2-2023
PubMedCentral® Full Text Version
Post-print
Abstract
Deletion of the nuclear hormone receptor small heterodimer partner (Shp) ameliorates the development of obesity and nonalcoholic steatohepatitis (NASH) in mice. Liver-specific SHP plays a significant role in this amelioration. The gut microbiota has been associated with these metabolic disorders, and the interplay between bile acids (BAs) and gut microbiota contributes to various metabolic disorders. Since hepatic SHP is recognized as a critical regulator in BA synthesis, we assessed the involvement of gut microbiota in the antiobesity and anti-NASH phenotype of Shp−/− mice. Shp deletion significantly altered the levels of a few conjugated BAs. Sequencing the 16S rRNA gene in fecal samples collected from separately housed mice revealed apparent dysbiosis in Shp−/− mice. Cohousing Shp−/− mice with WT mice during a Western diet regimen impaired their metabolic improvement and effectively disrupted their distinctive microbiome structure, which became indistinguishable from that of WT mice. While the Western diet challenge significantly increased lipopolysaccharide and phenylacetic acid (PAA) levels in the blood of WT mice, their levels were not increased in Shp−/− mice. PAA was strongly associated with hepatic peroxisome proliferator-activated receptor gamma isoform 2 (Pparg2) activation in mice, which may represent the basis of the molecular mechanism underlying the association of gut bacteria and hepatic steatosis. Shp deletion reshapes the gut microbiota possibly by altering BAs. While lipopolysaccharide and PAA are the major driving forces derived from gut microbiota for NASH development, Shp deletion decreases these signaling molecules via dysbiosis, thereby partially protecting mice from diet-induced metabolic disorders.
Keywords
Animals, Mice, Bile Acids and Salts, Dysbiosis, Lipopolysaccharides, Liver, Metabolic Diseases, Mice, Inbred C57BL, Non-alcoholic Fatty Liver Disease, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Receptors, Cytoplasmic and Nuclear, RNA, Ribosomal, 16S, bile acids and salts, inflammation, intestine, liver, nuclear receptor/RXR, PPARs, microbiome, lipopolysaccharide, phenylacetic acid, small heterodimer partner
Published Open-Access
yes
Recommended Citation
Mifflin, Ryan; Park, Jung Eun; Lee, Mikang; et al., "Microbial Products Linked to Steatohepatitis Are Reduced by Deletion of Nuclear Hormone Receptor SHP in Mice" (2023). Faculty and Staff Publications. 5620.
https://digitalcommons.library.tmc.edu/baylor_docs/5620
Included in
Allergy and Immunology Commons, Biological Phenomena, Cell Phenomena, and Immunity Commons, Pathology Commons