The liver is the main tissue site of vitamin A storage in the body and the hepatic stellate cell (HSC) (also referred to as Ito cell, fat-storing cell or lipocyte) is the major cellular site of vitamin A storage within the liver. Liver vitamin A stores serve as a buffer to prevent the adverse consequences of both insufficient and excessive dietary vitamin A intake. Nearly all hepatic vitamin A is found in the large cytoplasmic lipid droplets (LDs) present in HSCs. The number, size and vitamin A (retinyl ester) content of these LDs increases in response to greater dietary vitamin A intake and decreases in times of insufficient dietary intake. HSC LDs are a specialized subcellular organelle that has as its' only known physiologic function to facilitate vitamin A storage. This is unlike other hepatic LDs, for instance the LDs in hepatocytes, which have a more generalized role in neutral lipid (triglyceride and cholesterol) storage and metabolism. The relatively large retinyl ester content of HSC LDs and their responsiveness to dietary vitamin A intake render them very distinct from other LDs that are present in other cell types of the body. Yet little is known about the genesis or maintenance of HSC LDs or the biochemical and molecular events that are essential for this. Our studies will establish the biochemical and molecular processes that are essential for HSC LD formation and maintenance and how these are linked to vitamin A storage and mobilization from the liver. This project will address 3 fundamental questions regarding HSC LD biochemistry and vitamin A storage and metabolism in the liver.
Aim 1 proposes characterization and study of the proteome of mouse HSC LDs in times of excessive, normal (control) or insufficient vitamin A dietary intake. The studies proposed in Aim 2 grow out of our published research showing that that mice lacking lecithin:retinol acyltransferase (LRAT), the enzyme responsible for retinyl ester formation in HSCs, also lack LDs in HSCs but not hepatocytes. This is very surprising since, for a rodent maintained on a control diet, retinyl ester accounts for less than 40% of the total lipid present in the droplets.
In Aim 2 we propose to investigate why LRAT is needed for HSC LD formation. Finally, in Aim 3 we will investigate how vitamin A is mobilized from HSCs and whether this requires direct involvement of serum retinol-binding protein (RBP) synthesized in hepatocytes. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK079221-01
Application #
7302467
Study Section
Special Emphasis Panel (ZRG1-EMNR-G (03))
Program Officer
May, Michael K
Project Start
2007-08-15
Project End
2011-07-31
Budget Start
2007-08-15
Budget End
2008-07-31
Support Year
1
Fiscal Year
2007
Total Cost
$321,708
Indirect Cost
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Clugston, Robin D; Huang, Li-Shin; Blaner, William S (2015) Chronic alcohol consumption has a biphasic effect on hepatic retinoid loss. FASEB J 29:3654-67
Brun, Pierre-Jacques; Grijalva, Ambar; Rausch, Richard et al. (2015) Retinoic acid receptor signaling is required to maintain glucose-stimulated insulin secretion and ?-cell mass. FASEB J 29:671-83
Shmarakov, Igor O; Borschovetska, Vira L; Marchenko, Mykhailo M et al. (2014) Retinoids modulate thioacetamide-induced acute hepatotoxicity. Toxicol Sci 139:284-92
Clugston, Robin D; Yuen, Jason J; Hu, Yunying et al. (2014) CD36-deficient mice are resistant to alcohol- and high-carbohydrate-induced hepatic steatosis. J Lipid Res 55:239-46
Li, Yang; Wongsiriroj, Nuttaporn; Blaner, William S (2014) The multifaceted nature of retinoid transport and metabolism. Hepatobiliary Surg Nutr 3:126-39
Wongsiriroj, Nuttaporn; Jiang, Hongfeng; Piantedosi, Roseann et al. (2014) Genetic dissection of retinoid esterification and accumulation in the liver and adipose tissue. J Lipid Res 55:104-14
Clugston, Robin D; Blaner, William S (2014) Vitamin A (retinoid) metabolism and actions: What we know and what we need to know about amphibians. Zoo Biol 33:527-35
Brun, Pierre-Jacques; Yang, Kryscilla Jian Zhang; Lee, Seung-Ah et al. (2013) Retinoids: Potent regulators of metabolism. Biofactors 39:151-63
Shmarakov, Igor O; Jiang, Hongfeng; Yang, Kryscilla Jian Zhang et al. (2013) Hepatic retinoid stores are required for normal liver regeneration. J Lipid Res 54:893-908
Clugston, Robin D; Jiang, Hongfeng; Lee, Man Xia et al. (2013) Altered hepatic retinyl ester concentration and acyl composition in response to alcohol consumption. Biochim Biophys Acta 1831:1276-86

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