PMID- 29286303 OWN - NLM STAT- MEDLINE DCOM- 20180806 LR - 20181113 IS - 2072-6643 (Electronic) IS - 2072-6643 (Linking) VI - 10 IP - 1 DP - 2017 Dec 29 TI - Disturbed Vitamin A Metabolism in Non-Alcoholic Fatty Liver Disease (NAFLD). LID - 10.3390/nu10010029 [doi] LID - 29 AB - 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 mumol/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. FAU - Saeed, Ali AU - Saeed A AD - Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands. a.saeed@umcg.nl. AD - Institute of Molecular Biology & Bio-Technology, Bahauddin Zakariya University, Multan 60800, Pakistan. a.saeed@umcg.nl. FAU - Dullaart, Robin P F AU - Dullaart RPF AD - Department of Endocrinology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands. r.p.f.dullaart@umcg.nl. FAU - Schreuder, Tim C M A AU - Schreuder TCMA AD - Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands. t.c.m.a.schreuder@umcg.nl. FAU - Blokzijl, Hans AU - Blokzijl H AD - Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands. h.blokzijl@umcg.nl. FAU - Faber, Klaas Nico AU - Faber KN AD - Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands. k.n.faber@umcg.nl. AD - Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands. k.n.faber@umcg.nl. LA - eng PT - Journal Article PT - Review DEP - 20171229 PL - Switzerland TA - Nutrients JT - Nutrients JID - 101521595 RN - 0 (Membrane Proteins) RN - 0 (RBP4 protein, human) RN - 0 (Retinol-Binding Proteins, Plasma) RN - 11103-57-4 (Vitamin A) RN - EC 3.1.1.3 (Lipase) RN - EC 3.1.1.3 (adiponutrin, human) SB - IM MH - Adipose Tissue/metabolism/pathology MH - Animals MH - Cell Transdifferentiation MH - Genetic Predisposition to Disease MH - Genetic Variation MH - Hepatic Stellate Cells/metabolism/pathology MH - Homeostasis MH - Humans MH - Lipase/genetics/metabolism MH - Lipid Metabolism MH - Liver/drug effects/*metabolism/pathology/physiopathology MH - Membrane Proteins/genetics/metabolism MH - Myofibroblasts/metabolism/pathology MH - Non-alcoholic Fatty Liver Disease/drug therapy/genetics/*metabolism/physiopathology MH - Retinol-Binding Proteins, Plasma/metabolism MH - Risk Factors MH - Vitamin A/*metabolism/therapeutic use MH - Vitamin A Deficiency/drug therapy/genetics/*metabolism/physiopathology PMC - PMC5793257 OTO - NOTNLM OT - hepatic stellate cells OT - lipid metabolism OT - metabolic syndrome OT - non-alcoholic fatty liver disease OT - nuclear receptors OT - retinoic acid OT - retinol OT - retinol binding protein 4 OT - retinyl esters OT - vitamin A COIS- The authors certify that they have no affiliations with or involvement in any organization or entity with any financial or non-financial interest in the subject matter or materials described in this manuscript. EDAT- 2017/12/30 06:00 MHDA- 2018/08/07 06:00 PMCR- 2018/01/01 CRDT- 2017/12/30 06:00 PHST- 2017/11/07 00:00 [received] PHST- 2017/12/13 00:00 [revised] PHST- 2017/12/19 00:00 [accepted] PHST- 2017/12/30 06:00 [entrez] PHST- 2017/12/30 06:00 [pubmed] PHST- 2018/08/07 06:00 [medline] PHST- 2018/01/01 00:00 [pmc-release] AID - nu10010029 [pii] AID - nutrients-10-00029 [pii] AID - 10.3390/nu10010029 [doi] PST - epublish SO - Nutrients. 2017 Dec 29;10(1):29. doi: 10.3390/nu10010029.