Estimates of death rates caused by chronic alcohol consumption, published in 2004 by the World Health Organization, indicate that alcohol accounts for approximately 1.8 million deaths per year. Alcohol consumption leads to addiction and damage to almost every organ in the body. The molecular events that underlie alcohol-associated disease are complex and not completely understood. Retinoids (vitamin A and its metabolites) are potent transcriptional regulators that are needed for mediating normal cell proliferation, differentiation and apoptosis. One adverse action of alcohol involves promotion of tissue and organ damage by impairing retinoid metabolism and actions in liver (where 70% of the body's retinoid is stored) and in peripheral tissues. Alcoholics generally have very reduced hepatic and tissue retinoid levels. This results in decreased retinoid availability for maintaining normal cell proliferation and differentiation, rendering cells/tissues more susceptible to alcohol-induced injury. Reasons proposed in the literature to explain why retinoid homeostasis is impaired in alcoholics are: 1. alcohol inhibits the synthesis of the transcriptionally active retinoid, retinoic acid, by competing for alcohol (retinol) dehydrogenases and aldheyde (retinal) dehydrogenases catalyzing retinoic acid synthesis;2. alcohol accelerates retinoid oxidation, involving ethanol-inducible cytochromes like Cyp2E1;and 3. alcohol increases mobilization of stored retinoid from the liver to other tissues. It is currently believed by investigators working in the area of retinoid metabolism that the key metabolic events regulating retinoid homeostasis within cells/tissues are retinyl ester synthesis (involving lecithin:retinol acyltransferase or LRAT) and retinoic acid oxidation (catalyzed by cytochrome enzymes). It is further thought that hepatic retinoid metabolism is integrated with that of peripheral tissues, through rapid interorgan transfer of retinol mediate via retinol-binding protein (RBP). Our investigations will focus on hepatic retinoid storage and retinoid mobilization/redistribution from the liver and how these important regulatory processes are influenced by chronic alcohol intake. We will employ Lrat-/- and Rbp-/- mice and mice expressing lipoprotein lipase (LpL) solely in skeletal muscle (MCK-LpL0 mice) to investigate these relationships. We have studied and published descriptions of the characteristics of these mice with regards to retinoid storage, metabolism and transport and now propose to employ these mouse models to study alcohol-induced organ injury. LRAT is a central regulator of tissue/cellular retinoid homeostasis, controlling retinol availability for retinoic acid synthesis. Lrat-/- mice possess very little stored retinoid in any tissue, and none in liver. RBP is synthesized primarily by the liver and is the sole transport protein for retinol in the circulation, accounting for >95% of the retinoid present in the fasting circulation. Rbp-/- mice accumulate dietary retinoid normally in liver and are phenotypically normal when maintained on a retinoid-sufficient diet. However Rbp-/- mice are unable to mobilize/redistribute retinol from the liver to the periphery. LpL catalyzes the hydrolysis of retinyl esters and its expression is elevated over 30-fold in activated hepatic stellate cells (HSCs), the cellular site of retinoid storage in the liver. It has been proposed that LpL facilitates retinoid mobilization from HSC retinoid stores upon HSC activation. Hepatic retinoid storage and mobilization are normal in healthy MCK-LpL0 mice since serum and hepatic retinoid levels are not different for these mice compared to matched chow fed wild type (WT) mice. Thus, using MCK-LpL0 mice which are unable to express LpL in activated HSCs, we will be able to define a role for LpL in alcohol-induced liver disease. The project consists of 2 Aims.
In Aim 1 we will ask: How does the absence of hepatic retinoid stores influence alcohol-induced liver disease development and liver regeneration? These investigations will involve the use of Lrat-/- mice to explore the role that hepatic retinoid stores and LRAT have in the development of alcoholic liver disease.
In Aim 2 we will ask: Does the ability to mobilize/redistribute hepatic retinoid stores to the periphery contribute to the development of alcohol-induced tissue/organ injury? Here we will employ Rbp-/- mice, which are unable to mobilize hepatic retinoid stores, and MCK-LpL0 mice which can not express LpL in liver, an organ where it is proposed LpL plays a role in mobilizing hepatic retinyl ester stores upon hepatic injury. We will also explore in WT, Rbp-/- and MCK-LpL0 mice whether the ability to mobilize/redistribute hepatic retinoid stores contributes to the development of peripheral organ injury, specifically to alcoholic cardiomyopathy.
Chronic alcohol consumption is a major public health problem, leading to addiction and damage of almost every organ in the body. There is compelling evidence that alcohol impairs vitamin A metabolism in tissues, especially liver, where 70% of the vitamin A present in the body is stored. This results in lessened vitamin A availability for maintaining normal cellular proliferation, differentiation and apoptosis in liver and other organs. We are proposing studies that will provide a more complete understanding of relationships between alcohol consumption, vitamin A metabolism and actions, and alcoholic organ damage.
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