No 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.

Inclusion of RBP4 levels in traditional models enhances the predictive ability for the incidence of atherosclerotic events. RBP4 promotes atherogenesis by inducing macrophage-derived foam cell formation.

These results have unraveled a novel role of RBP4 in hepatic mitochondrial dysfunction and steatosis and suggest that RBP4 might be a potential target for the early prevention of NAFLD.

It has been suggested that retinoic acid (RA) has a potential role in the prevention of atherosclerotic CVD. In the present study, we used J774A.1 cell lines and primary peritoneal macrophages to investigate the protective effects of RA on foam cell formation and atherogenesis in apoE-deficient (apoE 2/2 ) mice. A total of twenty male apoE 2/2 mice (n 10 animals per group), aged 8 weeks, were fed on a high-fat diet (HFD) and treated with vehicle or 9-cis-RA for 8 weeks. The atherosclerotic plaque area in the aortic sinus of mice in the 9-cis-RA group was 40·7 % less than that of mice in the control group (P,0·01). Mouse peritoneal macrophages from the 9-cis-RA group had higher protein expression levels of ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1) than those from the control group. Serum total and LDL-cholesterol concentrations were lower in the 9-cis-RA group than in the control group (P, 0·05). In vitro studies showed that incubation of cholesterol-loaded J774A.1 macrophages with 9-cis-RA (0·1, 1 and 10 mmol/l) induced cholesterol efflux in a dose-dependent manner. The 9-cis-RA treatment markedly attenuated lipid accumulation in macrophages exposed to oxidised LDL. Moreover, treatment with 9-cis-RA significantly increased the protein expression levels of ABCA1 and ABCG1 in J774A.1 macrophages in a dose-dependent manner. Furthermore, 9-cis-RA dose-dependently enhanced the protein expression level of liver X receptor-a (LXRa), the upstream regulator of ABCA1 and ABCG1. Taken together, the present results show that 9-cis-RA suppresses foam cell formation and prevents HFD-induced atherogenesis via the LXRa-dependent up-regulation of ABCA1 and ABCG1.

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High 7-KC levels are associated with increased risk of cardiovascular events, total death, and composite outcomes in patients with stable coronary artery disease.

In multivariate analyses, the hazard ratios for total mortality among those in the lowest (referent) to highest quartiles of serum RA measured at study entry were 1.0, 0.83, 0.74, and 0.56, respectively (P-trend<0.001). For cardiovascular mortality, the comparable hazard ratios were 1.0, 0.76, 0.69, and 0.60 (P-trend<0.001). Furthermore, high RA levels (defined as >median) were associated with lower risk of total mortality (adjusted hazard ratios, 0.68; 95% confidence interval, 0.50-0.85; P=0.001) and cardiovascular mortality (adjusted hazard ratios, 0.62; 95% confidence interval, 0.45-0.78; P<0.001) compared with low RA (defined as ≤median). rodents. 14 Furthermore, all-trans RA treatment was shown to be effective in restoring the cardioprotective oxytocin-natriuretic peptides system and preventing abnormal cardiac remodeling in the ob/ob mice. 15 Our recent study showed that dietary supplementation of RA attenuated the development of atherosclerotic lesions in apolipoprotein E-deficient mice. 16 The improved effects of RA on cardiovascular diseases were further demonstrated in the in vitro studies that are involved in different types of cardiovascular cells. Activation of retinoid signaling effectively enhanced cholesterol efflux from cholesterol-loaded macrophage foam cells. [16][17][18] RA treatment inhibited the secretion of coagulatory factors from endothelial cells under proinflammatory conditions. Conclusions19 Thus, retinoid therapy may have important implications in limiting or regressing atherosclerotic cardiovascular disease.Although animal studies provided the appealing data that RA supplementation might be a promising therapeutic nutrient for cardiovascular disease, the clinical relevance of circulating RA in the cardiovascular disease have not been carefully investigated before. Therefore, in this study, we prospectively evaluated the relationship of serum RA with the risk of mortality in patients with coronary artery disease (CAD). Methods Study SubjectsStudy participants were recruited between October 2008 and December 2011 as part of the Expanded Guangdong Coronary Artery Disease Cohort (EGCADC).20-23 EGCADC consisted of patients aged from 40 to 80 years old recruited from GCADC and outpatients from Guangdong General Hospital following the same inclusion and exclusion criteria, ascertainment of CAD, questionnaires and study protocol. A total of 2523 CAD patients were included in the EGCADC (1513 from GCADC and another 1010 from Guangdong General Hospital). The patients will be enrolled if they met one of the following inclusion criteria: history of myocardial infarction (MI), angiographic evidence of >50% stenosis in ≥1 coronary vessels, evidence of exercise-induced ischemia by treadmill or nuclear testing, and history of coronary revascularization or documented diagnosis of CAD by an internist or cardiologist. Participants were excluded if they could not walk 1 block, had MI within the past 6 months, malignancy, with missing or incomplete angiographic data, missing blood samples, laboratory me...