Mechanisms of amelioration of NASH development by deletion of the orphan nuclear receptor SHP: interaction between bile acid and gut microbiota

Abstract

Whole‐body deletion of small heterodimer partner (SHP, NR0B2), an orphan nuclear receptor, protects mice from diet‐induced obesity and hepatic steatosis upon feeding of a western diet (WD). Additionally, a six‐month WD regimen promoted the progression of nonalcoholic steatohepatitis (NASH) in wild type C57BL/6 mice (WT). Interestingly, SHP deletion was also protective in progression of NASH, demonstrated by lower expression of inflammatory and fibrotic genes, reduced oxidative stress, and less macrophage infiltration in the liver of SHP−/− mice. To clarify its role in hepatic fibrosis, mice were challenged with methionine and choline deficient (MCD) diet for four weeks. While WT mice developed fibrosis after the MCD diet regimen, no fibrotic phenotype was evident in SHP−/− mice when analyzed with qPCR and sirus red staining. Importantly, the observed protection against NASH was recapitulated in liver‐specific SHP‐null mice, suggesting that hepatic SHP plays a role in NASH development. Hepatic SHP is a critical component in bile acid (BA) synthesis through direct regulation of Cyp7a1 gene expression, which encodes the rate‐limiting enzyme in BA synthesis. Since a strong interrelationship between BA and the gut bacteria has been suggested, changes in BA composition possibly alters the composition of the gut microbiome, thereby affecting liver physiology significantly in the SHP−/− mice. Therefore, we performed 16s rDNA pyrosequencing using DNA extracted from fecal samples and ran a principal coordinate analysis (PCoA) with the obtained taxonomic composition. Indeed, mice lacking SHP display a distinctly different microbiome from WT mice, characterized by distinct PCoA clustering and a decreased abundance ratio of the Firmicutes phylum compared to the Bacteroidetes phylum. Using fluorescent staining, we found that the deletion of SHP does not result in loss of fecal bacterial abundance when fed WD. To confirm a potential effect of the gut microbiome on the liver phenotype, WT and SHP−/− mice were cohoused and challenged with WD. This cohousing abolished the protective phenotypes against body weight gain, hepatic inflammation and oxidative stress induced by WD feeding but not hepatic steatosis in the SHP−/− mice. In addition, cohousing also eliminated the distinctiveness in taxonomic composition of gut bacteria. These results suggest a relationship between SHP and the gut microbiome in the development of DIO, inflammation, and nonalcoholic steatohepatitis.Support or Funding InformationThis work had been supported by the National Institutes of Health 344 Grant R01DK093774 (to YKL)