Review
Hepatic metabolism of retinoids and disease associations

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Abstract

The liver is the most important tissue site in the body for uptake of postprandial retinoid, as well as for retinoid storage. Within the liver, both hepatocytes and hepatic stellate cells (HSCs) are importantly involved in retinoid metabolism. Hepatocytes play an indispensable role in uptake and processing of dietary retinoid into the liver, and in synthesis and secretion of retinol-binding protein (RBP), which is required for mobilizing hepatic retinoid stores. HSCs are the central cellular site for retinoid storage in the healthy animal, accounting for as much as 50–60% of the total retinoid present in the entire body. The liver is also an important target organ for retinoid actions. Retinoic acid is synthesized in the liver and can interact with retinoid receptors which control expression of a large number of genes involved in hepatic processes. Altered retinoid metabolism and the accompanying dysregulation of retinoid signaling in the liver contribute to hepatic disease. This is related to HSCs, which contribute significantly to the development of hepatic disease when they undergo a process of cellular activation. HSC activation results in the loss of HSC retinoid stores and changes in extracellular matrix deposition leading to the onset of liver fibrosis. An association between hepatic disease progression and decreased hepatic retinoid storage has been demonstrated. In this review article, we summarize the essential role of the liver in retinoid metabolism and consider briefly associations between hepatic retinoid metabolism and disease. This article is part of a Special Issue entitled Retinoid and Lipid Metabolism.

Highlights

► Hepatocytes are responsible for the uptake and processing of postprandial retinoid into the liver. ► Hepatocytes secrete retinol-binding protein (RBP) from the liver and account for most RBP found in the circulation. ► Extrahepatic tissues store retinoid and can recycle this retinoid back to the liver. ► Hepatic stellate cells store more than 50% of all retinoid present in the body. ► Hepatic retinoid stores are lost during the development of hepatic diseases.

Section snippets

Overview

The liver is quantitatively the most important storage site for retinoid in the body [1], [2], [3]. It is also quantitatively the most important tissue site of postprandial retinoid uptake in the body, accounting for uptake of 66–75% of all of dietary retinoid that is absorbed by the intestine [1], [2], [3]. And, the liver is the major organ site for retinol-binding protein (RBP) synthesis and secretion, accounting for 70–80% of all RBP that is normally present in the circulation [4], [5]. Note

Hepatic metabolism

There are two hepatic cell types centrally involved in retinoid processing and storage: the parenchymal cells (also known as hepatocytes) and HSCs [12]. The hepatocytes account for approximately 67% of all cells present in the liver and approximately 90% of hepatic protein; whereas the HSCs account for only approximately 8% of total hepatic cells and 1% of hepatic protein [10], [11]. It is well-established that hepatocytes are critically involved in the uptake and processing of dietary retinol

Associations between hepatic retinoid physiology and disease

As mentioned earlier, the liver is the major organ site for retinoid uptake from the diet, retinoid storage and retinol mobilization. These processes involve primarily retinol and retinyl esters. But the liver also contains enzymes which are capable of retinoic acid synthesis, retinoic acid catabolism and excretion [82]. The liver also expresses all 3 retinoic acid receptors (RARs) and all 3 retinoid X receptors (RXRs) [7]. Retinoic acid can undergo catabolism in the liver to more polar

Acknowledgements

The authors wish to acknowledge the support of grants RC2 AA019413, R01 DK68437, and R01 DK079221 from the National Institutes of Health which supported the research carried out in their laboratory and which was cited in this review.

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    1

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