Investigating the Intestine‐Specific Role of Small Heterodimer Partner

Abstract

Bile Acid (BA) is an essential physiological detergent synthesized in the liver and secreted into the intestine to help digest and absorb dietary lipids and nutrients. After aiding in digestion, BAs are reabsorbed and recycled back to the liver in a process called enterohepatic recirculation. Nuclear receptor called Small Heterodimer Partner (SHP) plays a fundamental role in coordinating this process. Although extensively studied in the liver, the role for SHP has not been elucidated in the intestine. Therefore, we generated and characterized the intestinal‐specific Shp knockout (IShpKO) mice. We challenged the control Floxed Shp (f/f Shp) and IShpKO with 1% Cholic Acid (CA) diet for 5 days and collected the liver and the intestine in fed and 6 hour fasted conditions. The gross phenotype (i.e. body weight change, liver‐to‐body weight ratio, intestinal length) was not altered with the loss of Shp but showed alterations when challenged with CA diet. Notably, the BA levels were increased in both the serum and intestine while triglyceride levels were increased in the serum under the absence of Shp on 1% CA diet. Despite changes in BA levels, the transcript levels of transporters and BA synthetic genes in the liver maintained their suppression upon CA feeding. This result suggests that loss of intestinal Shp does not affect liver Shp functions. However, we found that Shp‐mediated regulation of BA homeostasis was different in fed versus 6 hour fasted states. In contrast, the mRNA transcript levels in the intestine revealed that the loss of Shp misregulated the expression of BA regulators and transporters. Furthermore, region‐specific expression analysis revealed that many of the transporters and essential BA regulators including Shp are expressed in the ileum. Also, serum triglyceride levels were higher in the IShpKO group with and without excess CA diet after olive oil gavage, suggesting either (i) increased expression of fatty acid transporters or (ii) leaky gut secondary to excess BAs in IShpKO mice. To test the pathological consequence of Shp deletion in the intestine, we challenged mice with 2% Dextran sulfate Sodium (DSS) to induce colitis and found that IShpKO mice were more susceptible to intestinal damage. Taken together, we showed that Shp is a major regulator of intestinal barrier and nutrient absorption.Support or Funding InformationNational Institutes of Health (NIH) Research Grant Program (R01)