Association of serum retinoic acid with hepatic steatosis and liver injury in nonalcoholic fatty liver disease

Abstract

Background: Retinoic acid (RA), an active metabolite of vitamin A (retinol), has been implicated in the regulation of lipid metabolism and hepatic steatosis in animal models. However, the relation between RA and liver histology in patients with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is unknown. Objective: This study aimed at examining the association of RA with NAFLD and NASH in Chinese subjects. Design: Serum RA concentration was determined by ELISA in 41 control subjects, 45 patients with NAFLD, and 38 patients with NASH. The associations of RA with adiposity, serum glucose, lipid profiles, and markers of liver damage were studied. Moreover, both mRNA and protein levels of retinoic X receptor a (RXRa) in the liver were analyzed in subjects with different degrees of hepatic steatosis. Results: Serum RA concentrations in patients with NAFLD (1.42 6 0.47 ng/mL) and NASH (1.14 6 0.26 ng/mL) were significantly lower than those in control subjects (2.70 6 0.52 ng/mL) (P , 0.01). Furthermore, serum RA concentrations were significantly different between subjects with normal glucose tolerance and those with type 2 diabetes in control [2.87 6 0.52 (n = 28) vs. 2.32 6 0.44 ng/mL (n = 13)], NAFLD [1.61 6 0.37 (n = 29) vs. 1.28 6 0.41 ng/mL (n = 16)], and NASH [1.35 6 0.34 (n = 24) vs. 1.07 6 0.29 ng/mL (n = 14)] groups. In human liver tissue, RXRa mRNA expression was inversely correlated with the exacerbation of hepatic steatosis. Both serum RA concentrations and RXRa mRNA levels were inversely correlated with intrahepatic triglyceride content (r = -0.700, P , 0.001, and r = -0.611, P = 0.002, respectively). Compared with grade 0 severity, the concentration of RXRa protein was lower in more severe grades in patients with NAFLD. Conclusion: These results show that circulating RA concentrations were lower in subjects with NAFLD and were associated with hepatic lipid metabolism and insulin resistance. This trial was registered at clinicaltrials.gov as NCT01940263.Am J Clin Nutr 2015;102:130-7.

All-Trans-Retinoic Acid Enhances Mitochondrial Function in Models of Human Liver

“…Altered vitamin A homeostasis is well documented in alcoholic liver disease, but recent reports associate altered vitamin A homeostasis also with NAFLD and steatosis (Ashla et al, 2010;Kim et al, 2014;Liu et al, 2015;Trasino et al, 2015). For example, human liver biopsies of NAFLD and nonalcoholic steatohepatitis patients demonstrated increased expression of the main enzyme metabolizing atRA, CYP26A1, suggesting that atRA is depleted in livers of these patients (Ashla et al, 2010).…”

“…In addition, in a panel of human livers with increasing level of steatosis, retinol and retinyl ester concentrations and RARb mRNA decreased significantly with increasing steatosis (Trasino et al, 2015). Finally, in a study of patients with NAFLD and steatosis, retinoic acid (RA) concentrations were significantly lower in plasma from patients than in healthy controls (Liu et al, 2015). Yet detailed studies of retinoid signaling in models of NAFLD have not been conducted.…”

Association of Serum Retinoic Acid With Risk of Mortality in Patients With Coronary Artery Disease

“…The coefficient of variation for the interassay replicate samples was <8%. 29 We further validated the measurement of serum RA level by using gas chromatography-mass spectrometry method according to the previous report. 30 The duplicate measures of serum RA duplicates across the entire CAD case-control cohort were highly correlated (r=0.86).…”

Low Levels of Serum β-Carotene and β-Carotene/Retinol Ratio Are Associated with Histological Severity in Nonalcoholic Fatty Liver Disease Patients

“…NAFLD patients showed a decreased retinoic acid, which was inversely associated with hepatic SS and liver injury [18]. As the precursor of retinol acid, β-carotene may be involved in NAFLD occurrence and development.…”