It is well established that chylomicron remnant (dietary) vitamin A is taken up from the circulation by hepatocytes, but more than 80 % of the vitamin A in the liver is stored in hepatic stellate cells (HSC). It presently is not known how vitamin A is transferred from hepatocytes to HSCs for storage. Since retinol-binding protein 4 (RBP4), a protein that is required for mobilizing stored vitamin A, is synthesized solely by hepatocytes and not HSCs, it similarly is not known how vitamin A is transferred from HSCs to hepatocytes. Although it has long been thought that RBP4 is absolutely essential for delivering vitamin A to tissues, recent research has proven that this notion is incorrect since total RBP4-deficiency is not lethal. In addition to RBP4, vitamin A is also found in the circulation bound to lipoproteins and as retinoic acid bound to albumin. It is not known how these different circulating pools of vitamin A contribute to the vitamin A needs of different tissues. In our view, better insight into these three issues is required to better understand vitamin A absorption, storage and mobilization. Here, we provide an up to date synthesis of current knowledge regarding the intestinal uptake of dietary vitamin A, the storage of vitamin A within the liver, and the mobilization of hepatic vitamin A stores, and summarize areas where our understanding of these processes is incomplete.

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There is considerable evidence that both retinoids and retinol-binding protein 4 (RBP4) contribute to the development of liver disease. To understand the basis for this, we generated and studied transgenic mice that express human RBP4 (hRBP4) specifically in adipocytes (adi-hRBP4 mice). When fed a chow diet, these mice show an elevation in adipose total RBP4 (mRBP4 + hRBP4) protein levels. However, no significant differences in plasma RBP4 or retinol levels, or differences in hepatic or adipose retinoid (retinol, retinyl ester, and all-trans-retinoic acid) levels were observed. Strikingly, male adi-hRBP4 mice fed a standard chow diet display significantly elevated hepatic triglyceride levels at 3-4 months of age compared to matched littermate controls. When mice were fed a high-fat diet, this hepatic phenotype, as well as other metabolic phenotypes (obesity and glucose intolerance) worsened. Since adi-hRBP4 mice have increased TNFα and leptin expression and crown-like structures in adipose tissue, our data are consistent with the notion that adipose tissue is experiencing RBP4-induced inflammation that stimulates increased lipolysis within adipocytes. Our data further establish that elevated hepatic triglyceride levels result from increased hepatic uptake of adipose-derived circulating free fatty acids (FFAs). We obtained no evidence that elevated hepatic triglyceride levels arise from increased hepatic de novo lipogenesis, or decreased hepatic FFA oxidation, or decreased very low density lipoprotein (VLDL) secretion. Conclusion Our investigations establish that RBP4 expressed in adipocytes induces hepatic steatosis arising from primary effects occurring in adipose tissue.

Acyl CoA:diacylglycerol acyltransferase (DGAT) 1 catalyzes the final step of triglyceride (TG) synthesis. We show that acute administration of a DGAT1 inhibitor (DGAT1i) by oral gavage or genetic deletion of intestinal Dgat1 (intestine-Dgat1−/−) markedly reduced postprandial plasma TG and retinyl ester excursions by inhibiting chylomicron secretion in mice. Loss of DGAT1 activity did not affect the efficiency of retinol esterification, but it did reduce TG and retinoid accumulation in the small intestine. In contrast, inhibition of microsomal triglyceride transfer protein (MTP) reduced chylomicron secretion after oral fat/retinol loads, but with accumulation of dietary TG and retinoids in the small intestine. Lack of intestinal accumulation of TG and retinoids in DGAT1i-treated or intestine-Dgat1−/− mice resulted, in part, from delayed gastric emptying associated with increased plasma levels of glucagon-like peptide (GLP)-1. However, neither bypassing the stomach through duodenal oil injection nor inhibiting the receptor for GLP-1 normalized postprandial TG or retinyl esters excursions in the absence of DGAT1 activity. In summary, intestinal DGAT1 inhibition or deficiency acutely delayed gastric emptying and inhibited chylomicron secretion; however, the latter occurred when gastric emptying was normal or when lipid was administered directly into the small intestine. Long-term hepatic retinoid metabolism was not impacted by DGAT1 inhibition.

Retinoids (vitamin A and its analogs) are highly potent regulators of cell differentiation, cell proliferation, and apoptosis. Because of these activities, retinoids have been most extensively studied in the contexts of embryonic development and of proliferative diseases, especially cancer and skin disease. Recently, there has been considerable new research interest focused on gaining understanding of the roles that retinoids and/or retinoid-related proteins may have in the development of metabolic diseases, primarily obesity, diabetes, and dyslipidemia. This review will summarize recent advances that have been made in these areas, focusing on the role of retinoids in modulating adipogenesis, the roles of retinoids and retinoid-related proteins as signaling molecules linking obesity with the development of type II diabetes, the roles of retinoids in pancreatic β-cell biology/insulin secretion, and the actions of retinoids in hepatic steatosis.