Gene Polymorphisms and Biological Effects of Vitamin D Receptor on Nonalcoholic Fatty Liver Disease Development and Progression

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, with increasing prevalence worldwide. The genetic and molecular background of NAFLD pathogenesis is not yet clear. The vitamin D/vitamin D receptor (VDR) axis is significantly associated with the development and progression of NAFLD. Gene polymorphisms may influence the regulation of the VDR gene, although their biological significance remains to be elucidated. VDR gene polymorphisms are associated with the presence and severity of NAFLD, as they may influence the regulation of adipose tissue activity, fibrosis, and hepatocellular carcinoma (HCC) development. Vitamin D binds to the hepatic VDR to exert its biological functions, either by activating VDR transcriptional activity to regulate gene expression associated with inflammation and fibrosis or by inducing intracellular signal transduction through VDR-mediated activation of Ca2+ channels. VDR activity has protective and detrimental effects on hepatic steatosis, a characteristic feature of NAFLD. Vitamin D-VDR signaling may control the progression of NAFLD by regulating immune responses, lipotoxicity, and fibrogenesis. Elucidation of the genetic and molecular background of VDR in the pathophysiology of NAFLD will provide new therapeutic targets for this disease through the development of VDR agonists, which already showed promising results in vivo.

Association of the ESR1 (rs9340799), OLR1 (rs3736234), LIPC (rs2070895), VDR (rs2228570), and CETP (rs708272) Polymorphisms With Risk of Coronary Artery Disease in Iranian Patients

“…The rs2228570 polymorphism is located in the 3′‐untranslated region (UTR) of the VDR gene, which does not affect the protein's amino acid sequence but may affect mRNA stability or translation efficiency. The T‐allele or TT genotype may lead to reduced mRNA stability or translation efficiency, resulting in decreased expression of the VDR protein and potentially impaired vitamin D signaling and lipid metabolism [ 51 ]. The other four SNPs, ESR1 (rs9340799), OLR1 (rs3736234), LIPC (rs2070895), and CETP (rs708272), did not show any association with CAD risk.…”

“…genotype may lead to reduced mRNA stability or translation efficiency, resulting in decreased expression of the VDR protein and potentially impaired vitamin D signaling and lipid metabolism [51]. other four SNPs, ESR1 (rs9340799), OLR1 (rs3736234), LIPC (rs2070895), and CETP (rs708272), did not show any association with CAD risk.…”

Targeting nuclear receptors for NASH/MASH: From bench to bedside

“… 78 In humans, VDR polymorphisms and circulating vitamin D levels have been associated with the severity of MASLD. 79 – 82 Human studies suggest that although hepatic VDR expression is upregulated in benign steatosis, it is only modestly increased in individuals with MASH, indicating a temporal effect of VDR function in MASLD progression, in a tissue/cell-type specific manner. 70 However, as the role of VDRs vis à vis that of vitamin D in MASH is still debatable and unclear, there are currently no clinical trials targeting VDR for the treatment of MASLD/MASH.…”

Exploring the interactions between metabolic dysfunction-associated fatty liver disease and micronutrients: from molecular mechanisms to clinical applications

“…Polymorphisms in the Vitamin D receptor gene could explain the varied outcomes observed. While Vitamin D ameliorates liver damage in MAFLD, early expression of its receptor in MAFLD patients’ livers and decreased lipid accumulation in mice lacking this receptor gene point to its intricate involvement in MAFLD’s development and progression ( 87 ).…”