Biological Functions for STARD5 Assessed Using stard5−/− Mice

Abstract

STARD5 belongs to the StAR‐Related Lipid‐transfer (START) domain protein superfamily and is proposed to contribute to intracellular non‐vesicular cholesterol transport. STARD5 is a soluble sterol‐binding protein that is induced by endoplasmic reticulum (ER) stress, yet testing for a biological function needs to consider the conflicting data on whether the preferred ligand for STARD5 is cholesterol and 25‐hydroxycholesterol or bile acids, including chenodeoxycholic acid (CDCA). Our work has characterized STARD5 expression in kidney and we reported that STARD5 and cholesterol levels are increased in kidneys of the OVE diabetic mouse model compare to wild‐type controls, and that STARD5 is increased in cell culture by the ER stress inducer tunicamycin. Cholesterol accumulation in the ER is known to promote ER stress; however, the significance of the association between elevated renal cholesterol, ER stress, and STARD5 in diabetic kidney remains to be determined. We propose STARD5 indirectly controls cholesterol homeostasis via modulating farnesoid X receptor (FXR) activity. FXR is a nuclear receptor that binds CDCA and activation of FXR contributes to maintaining fatty acid and cholesterol homeostasis in diabetic kidney disease. To test whether STARD5 affects FXR signaling we generated whole body STARD5 knock‐out mice (stard5−/−) using CRISPR‐Cas9 and compared the FXR target gene expression in the knockout and WT kidney. There was no difference in body weight, liver weight/body weight ratio, or kidney weight/body weight ratio between stard5−/− mice compared to wild‐type littermate controls (WT) (male mice n = 5 WT; n= 7 stard5−/−). We will present data from current studies focused on determining whether there are differences in tissue histology, lipid accumulation, and FXR target gene expression between stard5−/− mice and WT littermate controls.Support or Funding InformationBiochemistry & Molecular Genetics Departmental Funds to BJC