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

Nutrients. 2017 Dec 29;10(1):29. doi: 10.3390/nu10010029.


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.

Publication types

  • Review

MeSH terms

  • Adipose Tissue / metabolism
  • Adipose Tissue / pathology
  • Animals
  • Cell Transdifferentiation
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Hepatic Stellate Cells / metabolism
  • Hepatic Stellate Cells / pathology
  • Homeostasis
  • Humans
  • Lipase / genetics
  • Lipase / metabolism
  • Lipid Metabolism
  • Liver / drug effects
  • Liver / metabolism*
  • Liver / pathology
  • Liver / physiopathology
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Myofibroblasts / metabolism
  • Myofibroblasts / pathology
  • Non-alcoholic Fatty Liver Disease / drug therapy
  • Non-alcoholic Fatty Liver Disease / genetics
  • Non-alcoholic Fatty Liver Disease / metabolism*
  • Non-alcoholic Fatty Liver Disease / physiopathology
  • Retinol-Binding Proteins, Plasma / metabolism
  • Risk Factors
  • Vitamin A / metabolism*
  • Vitamin A / therapeutic use
  • Vitamin A Deficiency / drug therapy
  • Vitamin A Deficiency / genetics
  • Vitamin A Deficiency / metabolism*
  • Vitamin A Deficiency / physiopathology


  • Membrane Proteins
  • RBP4 protein, human
  • Retinol-Binding Proteins, Plasma
  • Vitamin A
  • Lipase
  • adiponutrin, human