Abstract
Vitamin A is required for important physiological processes, including embryogenesis, vision, cell proliferation and differentiation, immune regulation, and glucose and lipid metabolism. Many of vitamin A’s functions are executed through retinoic acids that activate transcriptional networks controlled by retinoic acid receptors (RARs) and retinoid X receptors (RXRs).The liver plays a central role in vitamin A metabolism: (1) it produces bile supporting efficient intestinal absorption of fat-soluble nutrients like vitamin A; (2) it produces retinol binding protein 4 (RBP4) that distributes vitamin A, as retinol, to peripheral tissues; and (3) it harbors the largest body supply of vitamin A, mostly as retinyl esters, in hepatic stellate cells (HSCs). In times of inadequate dietary intake, the liver maintains stable circulating retinol levels of approximately 2 μmol/L, sufficient to provide the body with this vitamin for months. Liver diseases, in particular those leading to fibrosis and cirrhosis, are associated with impaired vitamin A homeostasis and may lead to vitamin A deficiency. Liver injury triggers HSCs to transdifferentiate to myofibroblasts that produce excessive amounts of extracellular matrix, leading to fibrosis. HSCs lose the retinyl ester stores in this process, ultimately leading to vitamin A deficiency. Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and is a spectrum of conditions ranging from benign hepatic steatosis to non-alcoholic steatohepatitis (NASH); it may progress to cirrhosis and liver cancer. NASH is projected to be the main cause of liver failure in the near future. Retinoic acids are key regulators of glucose and lipid metabolism in the liver and adipose tissue, but it is unknown whether impaired vitamin A homeostasis contributes to or suppresses the development of NAFLD. A genetic variant of patatin-like phospholipase domain-containing 3 (PNPLA3-I148M) is the most prominent heritable factor associated with NAFLD. Interestingly, PNPLA3 harbors retinyl ester hydrolase activity and PNPLA3-I148M is associated with low serum retinol level, but enhanced retinyl esters in the liver of NAFLD patients. Low circulating retinol in NAFLD may therefore not reflect true “vitamin A deficiency”, but rather disturbed vitamin A metabolism. Here, we summarize current knowledge about vitamin A metabolism in NAFLD and its putative role in the progression of liver disease, as well as the therapeutic potential of vitamin A metabolites.
Highlights
Since (1) dietary retinyl esters are first delivered to—and hydrolyzed—in hepatocytes before they move as retinol to hepatic stellate cells (HSCs) to become esterified again, and since (2) patatin-like phospholipase domain-containing 3 (PNPLA3) is expressed both in hepatocytes and HSC, it remains unclear which hepatic cell type retinyl esters accumulate in Non-alcoholic fatty liver disease (NAFLD) and in PNPLA3-I148M patients
Hepatic lipid content is a result of the following steps: (1) de novo lipogenesis (DNL) in the liver; (2) an influx of dietary lipids (delivered as non-esterified free fatty acids (NEFAs) or as TG in chylomicrons); (3) an influx of non-esterified fatty acids (NEFA) produced by adipose tissue (primarily from white adipose tissue (WAT)); (4) the esterification of lipids and packaging into lipid droplets; (5) an influx of TG carried in CM remnants and low density lipoproteins (LDL); (6) an efflux of TG carried in very low density lipoprotein (VLDL)-particles; (7) TG hydrolysis producing NEFAs; and (8) catabolism of
Despite extensive historical and recent evidence that (1) vitamin A metabolism is disturbed in obesity and NAFLD and (2) vitamin A metabolites, especially atRA and synthetic retinoic acid receptors (RARs) ligands, have beneficial effects on hepatic lipid metabolism and obesity-induced NAFLD in animal models, no clinical trials are ongoing to evaluate their therapeutic potential in patients
Summary
NAFLD is characterized by the accumulation of fat in the liver, in in particular particular non-esterified non-esterified fatty acids (NEFA), triglycerides, cholesterol. In contrast to reduced retinol, serum levels of RBP4 are typically elevated in MetS patients and obese animals. It was found that hepatocyte-specific deletion of Rbp in mice completely abolishes RBP4 from the circulation, both in lean and obese animals, providing strong evidence that the liver, the hepatocytes, is the primary—if not sole—source of serum RBP4 [87] In line with this finding is that adipocyte-specific overexpression of human RBP4 did not increase circulating RBP4, but did cause hepatic steatosis in mice [88]. Hepatic RBP4 retention in low-retinol NAFLD livers suggests that impaired renal clearance might even be a more prominent factor in enhancing serum RBP4 levels. Serum RBP4 declines after this treatment, but this is not consistently associated with an improvement in insulin sensitivity [104,105,106,107]
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