The liver is the key organ in the body that regulates vitamin A homeostasis. It is the tissue where approximately 75% of newly absorbed dietary vitamin A is taken up; the site where approximately 80-90% of the vitamin A present in the body of a healthy well nourished individual is stored; and the site from which stored vitamin A is mobilized to meet the needs of extrahepatic tissues. Newly absorbed vitamin A arriving as retinyl ester in chylomicron remnants is taken up by hepatocytes and must be hydrolyzed to retinol before it is transferred to hepatic stellate cells (HSCs) for storage. Approximately 80% of hepatic vitamin A exists as retinyl ester in the lipid droplets of HSCs. HSC retinyl ester stores must be hydrolyzed to retinol so that vitamin A can be mobilized into the circulation bound to retinol-binding protein (RBP). Although there has been longstanding research interest focused on identifying the hepatic enzyme(s) responsible for catalyzing retinyl ester hydrolysis, the molecular identity(ies) of this enzyme(s) remains elusive. Our overall goal is to identify at the molecular level the enzyme(s) responsible in vivo for hydrolyzing chylomicron remnant retinyl ester in hepatocytes and lipid droplet retinyl esters in HSCs. The molecular identify of the enzyme which catalyzes retinyl ester hydrolysis in HSC lipid droplets and the factors that modulate hepatic retinol mobilization will be explored in Specific Aim 1. The molecular identity of the enzyme which catalyzes hydrolysis of newly absorbed chylomicron retinyl ester will be investigated in Specific Aim 2. Clinical Relevance. Over the past decade, a large literature reporting relationships between high blood retinol and RBP levels and metabolic disease, especially obesity, insulin resistance, liver disease, and cardiovascular disease has accumulated. Most of this literature consists of retrospective and prospective studies of human cohorts, but animal model and cell culture studies also point to these same relationships. Yet, the factors which control retinol and RBP release from the liver, and consequently blood levels, are not understood at the molecular level. We are proposing to investigate an enzymatic process, hepatic retinyl ester hydrolysis, that is essential to the regulation of blood retinol and RBP levels. Global Health Relevance. Vitamin A-deficiency remains a major global health problem. The World Health Organization estimates that millions of infants and young children worldwide are at risk of vitamin A-deficiency. We are proposing to study a process, the hydrolysis of hepatic vitamin A esters, that is central for allowing the body to maintain normal blood and tissue vitamin A levels, thus preventing vitamin A-deficiency. Our studies will advance understanding of an enzymatic process that is critical for allowing vitamin A to be accumulated in the liver and to be mobilized from the liver in order to keep cells and tissues healthy.

Public Health Relevance

The physiologically important enzymes in the liver that are responsible for the hydrolysis of vitamin A esters are not known. Investigations aimed at identifying and understanding physiologically important hepatic vitamin A ester hydrolases involved in these processes are being proposed. This information is of considerable Public Health and Clinical significance for understanding how blood levels of vitamin A are maintained and regulated.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK101251-02
Application #
9250768
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Maruvada, Padma
Project Start
2016-04-01
Project End
2019-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
2
Fiscal Year
2017
Total Cost
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
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Belyaeva, Olga V; Wu, Lizhi; Shmarakov, Igor et al. (2018) Retinol dehydrogenase 11 is essential for the maintenance of retinol homeostasis in liver and testis in mice. J Biol Chem 293:6996-7007
Blaner, William S (2018) Hepatic Stellate Cells (HSCs) and Retinoids: Towards A Much More Defined Relationship. Hepatology :
Blaner, William S (2017) Acyl-CoA wax alcohol acyltransferase 2: its regulation and actions in support of color vision. J Lipid Res 58:633-635
Thompson, Spencer J; Sargsyan, Ashot; Lee, Seung-Ah et al. (2017) Hepatocytes Are the Principal Source of Circulating RBP4 in Mice. Diabetes 66:58-63
Blaner, William S (2017) Retinoid Actions: A New Horizon. Endocrinology 158:2719-2721
Blaner, William S; Gao, Madeleine A; Jiang, Hongfeng et al. (2017) Chronic alcohol consumption decreases brown adipose tissue mass and disrupts thermoregulation: a possible role for altered retinoid signaling. Sci Rep 7:43474
Libien, J; Kupersmith, M J; Blaner, W et al. (2017) Role of vitamin A metabolism in IIH: Results from the idiopathic intracranial hypertension treatment trial. J Neurol Sci 372:78-84
Clugston, Robin D; Gao, Madeleine A; Blaner, William S (2017) The Hepatic Lipidome: A Gateway to Understanding the Pathogenes is of Alcohol-Induced Fatty Liver. Curr Mol Pharmacol 10:195-206
Ideta, Takayasu; Shirakami, Yohei; Ohnishi, Masaya et al. (2017) Non-alcoholic steatohepatitis-related liver tumorigenesis is suppressed in mice lacking hepatic retinoid storage. Oncotarget 8:70695-70706

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