Cholesterol homeostasis is maintained through the coordinated regulation of cholesterol uptake, synthesis, transport, esterification, secretion, and degradation. Recent advances have led to a more complete understanding of the way cholesterol's sorting and transport contribute to the maintenance of cholesterol homeostasis. However, the role of many intracellular cholesterol- binding proteins within various cells in the body, and their effect on cholesterol metabolism/degradation, remains unknown. The overall aim of this application is to elucidate the role of two START domain proteins (StarD4, StarD5) play in cholesterol and bile acid homeostasis in hepatocytes and macrophages using both in vitro and in vivo models. The P.I.s'labs have recently shown that cholesterol transport to the inner mitochondrial membrane represents the rate-determining step controlling bile acid synthesis via the 'acidic'pathway, and that the 'acidic'pathway is able to control nuclear levels of the known regulatory oxysterols, 27-hydroxycholesterol, 25-hydroxycholesterol, and at least one novel sulfated oxysterol. In addition to StarD1, there exists a family of proteins containing a StarD1 homologue domain that potentially is capable of binding and transporting sterols within cells. All proteins in this family have a similar structural lipid-binding domain referred to as the StarD1- related lipid transfer (START) domain. Most recently, they have also shown the following: 1) a coordinated response in the levels of StarD1, 27-hydroxycholesterol, and StarD5;2) an intracellular redistribution of StarD5 protein from the Golgi to the plasma membrane in response to cholesterol;3) that cholesterol is a ligand for both StarD4 and StarD5;the later also binds 25- hydroxycholesterol;and, 4) an increase in bile acid synthesis and cholesterol ester formation following StarD4 overexpression. In the studies proposed in this application, in vitro and in vivo models will be used to study the regulation, and physiological function of StarD4, and StarD5 in hepatocytes and in macrophages. Specifically, studies are proposed to: 1) characterize the regulation and subcellular movement of StarD4 and StarD5 in macrophages and hepatocytes (StarD4) in response to cholesterol;2) characterize the function of StarD4, and StarD5 in macrophages and hepatocytes (StarD4);3) characterize the physiological role(s) of StarD4 in cholesterol homeostasis in vivo. An understanding of the mechanisms of regulation of cholesterol homeostasis in hepatocytes and macrophages is very relevant to the understanding of the development of arteriosclerosis and heart disease in humans.

Public Health Relevance

Bile acids are required for intestinal absorption and solubilization of cholesterol and fats. In addition, bile acids play an additional crucial role in cholesterol homeostasis. Bile acids are made from cholesterol. Because cholestrol is not soluble in water, it binds to proteins to move within the cell. We propose to study novel proteins that bind and transport cholesterol within the cell and, among other things, regulate the bile acid biosynthetic pathway. The successful completion of this study will provide us with new insights into the molecular mechanisms involved in the regulation of bile acid biosynthesis and cholesterol homeostasis.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Hepatobiliary Pathophysiology Study Section (HBPP)
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Sherker, Averell H
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Virginia Commonwealth University
Internal Medicine/Medicine
Schools of Medicine
United States
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Calderon-Dominguez, Maria; Gil, Gregorio; Medina, Miguel Angel et al. (2014) The StarD4 subfamily of steroidogenic acute regulatory-related lipid transfer (START) domain proteins: new players in cholesterol metabolism. Int J Biochem Cell Biol 49:64-8
Rodriguez-Agudo, Daniel; Calderon-Dominguez, Maria; Medina, Miguel Angel et al. (2012) ER stress increases StarD5 expression by stabilizing its mRNA and leads to relocalization of its protein from the nucleus to the membranes. J Lipid Res 53:2708-15
Rodriguez-Agudo, Daniel; Calderon-Dominguez, Maria; Ren, Shunlin et al. (2011) Subcellular localization and regulation of StarD4 protein in macrophages and fibroblasts. Biochim Biophys Acta 1811:597-606