Disturbed Vitamin A Metabolism in Non-Alcoholic Fatty Liver Disease (NAFLD)

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.

Keywords: hepatic stellate cells; lipid metabolism; metabolic syndrome; non-alcoholic fatty liver disease; nuclear receptors; retinoic acid; retinol; retinol binding protein 4; retinyl esters; vitamin A.

Figure 1

Schematic representation of intestinal vitamin A absorption, transport to, and storage in the liver and redistribution to peripheral tissues (see main text for details). Carotenes (from plants) and retinyl esters (from animals) are the main dietary sources of vitamin A (lower left corner). They are absorbed in the proximal small intestine and transported as retinyl esters in chylomicrons (CM) to the liver. Chylomicron remnants are taken up by hepatocytes and retinyl esters are hydrolyzed to form retinol. Hepatocytes produce retinol binding protein 4 (RBP4) and retinol binding to RBP4 stimulates the secretion of retinol-carrying holo-RBP4 to the circulation. Retinol is then either transported to hepatic stellate cells for storage as retinyl esters or transported to peripheral tissues where it is converted to retinoic acids that activate the transcription factors retinoic acid receptor (RAR) or retinoid X receptor (RXR). In times of inadequate vitamin A intake, retinol is released from the HSC stores to maintain stable levels of circulating retinol (~2 μM in human).

Figure 2

Regulation of hepatic lipid metabolism by vitamin A metabolites. Triglyceride synthesis and breakdown is subdivided into eight steps: (1) de novo lipogenesis (DNL) in the liver, (2) influx of dietary lipids (delivered as non-esterified free fatty acids (NEFAs) or as triglycerides (TG) in chylomicrons), (3) influx of NEFAs produced by adipose tissue (primarily from white adipose tissue (WAT)), (4) esterification of lipids (mainly to TG) and packaging into lipid droplets, (5) influx of TG carried in CM remnants and low density lipoproteins (LDL), (6) efflux of TG carried in very low density lipoprotein (VLDL)-particles, (7) TG hydrolysis producing NEFAs, and (8) catabolism of NEFAs through mitochondrial and peroxisomal β-oxidation. Direct transcriptional regulation of lipogenic/lipolytic genes is shown in the inner (light gray) ring. Indirect transcriptional regulation is shown inside or outside the outer (dark gray) ring. Vitamin A-related factors are indicated in blue. Factors that promote lipogenesis are shown in red; factors promoting lipolysis in green. Relevant regulation and factors in adipose tissue and the intestine are also included (see main text for details about the specific genes that are regulated in each step). Additional abbreviations: FXR—Farnesoid X Receptor, SHP—Small Heterodimer Partner 1, HES6—Hes family BHLH transcription factor 6, HNF4α—Hepatocyte Nuclear Factor 4 alpha, LXR—Liver X Receptor, PPARγ—Peroxisome Proliferator-Activated Receptor gamma, chREBP—carbohydrate Response Element Binding Protein, SREBP-1c—Sterol Response Element Binding Protein-1c, PGC-1α—PPARγ-Coactivator 1-alpha, FGF—Fibroblast Growth Factor, BAT—Brown Adipose Tissue.