Protective effects of the succinate/SUCNR1 axis on damaged hepatocytes in NAFLD.

OBJECTIVE: Succinate and succinate receptor 1 (SUCNR1) are linked to fibrotic remodeling in models of non-alcoholic fatty liver disease (NAFLD), but whether they have roles beyond the activation of hepatic stellate cells remains unexplored. We investigated the succinate/SUCNR1 axis in the context of NAFLD specifically in hepatocytes. METHODS: We studied the phenotype of wild-type and Sucnr1-/- mice fed a choline-deficient high-fat diet to induce non-alcoholic steatohepatitis (NASH), and explored the function of SUCNR1 in murine primary hepatocytes and human HepG2 cells treated with palmitic acid. Lastly, plasma succinate and hepatic SUCNR1 expression were analyzed in four independent cohorts of patients in different NAFLD stages. RESULTS: Sucnr1 was upregulated in murine liver and primary hepatocytes in response to diet-induced NASH. Sucnr1 deficiency provoked both beneficial (reduced fibrosis and endoplasmic reticulum stress) and detrimental (exacerbated steatosis and inflammation and reduced glycogen content) effects in the liver, and disrupted glucose homeostasis. Studies in vitro revealed that hepatocyte injury increased Sucnr1 expression, which when activated improved lipid and glycogen homeostasis in damaged hepatocytes. In humans, SUCNR1 expression was a good determinant of NAFLD progression to advanced stages. In a population at risk of NAFLD, circulating succinate was elevated in patients with a fatty liver index (FLI) ≥60. Indeed, succinate had good predictive value for steatosis diagnosed by FLI, and improved the prediction of moderate/severe steatosis through biopsy when added to an FLI algorithm. CONCLUSIONS: We identify hepatocytes as target cells of extracellular succinate during NAFLD progression and uncover a hitherto unknown function for SUCNR1 as a regulator of hepatocyte glucose and lipid metabolism. Our clinical data highlight the potential of succinate and hepatic SUCNR1 expression as markers to diagnose fatty liver and NASH, respectively.

Current trends in access to treatment for hepatitis B in immigrants vs non-immigrants.

BACKGROUND: Universal vaccination for hepatitis B virus (HBV) and migratory movements have changed the demographic characteristics of this disease in Spain and in Europe. Therefore, we evaluated the characteristics of the disease and the possible differences according to origin (immigrants vs non-immigrants) and access to treatment. METHODS: This is a multicenter cross-sectional study (June 2014 to May 2015) in which outpatients with a positive HBsAg were seen and followed in four Hepatology units. Demographic and clinical data and indication and access to treatment were collected in two different regions of Catalonia (Spain) where there are no barriers to treatment due to a comprehensive coverage under the National Health System. RESULTS: A total of 951 patients were evaluated (48.1% men). Of these, 46.6% were immigrants (58.7% of them were born in Africa) and were significantly younger compared to non-immigrants. The proportions of patients with alcohol consumption, being overweight, and other indicators of metabolic co-morbidities were significantly higher in non-immigrants. Among the 937 patients receiving HBeAg examination, 91.7% were HBeAg-negative. Chronic HBeAg-positive infection was significantly higher in immigrants (3.9% vs 0.6%, P = 0.001) and chronic HBeAg-negative hepatitis was higher non-immigrants (31.7% vs 21.4%, P < 0.001). Not only was the proportion of patients who met treatment criteria significantly higher among non-immigrants (38.4% vs 29.2%, P = 0.003), but also the proportion of those with indication of effectively receiving therapy at the time of data collection (83.2% vs 57.8 %, P < 0.001). CONCLUSIONS: The immigrant population with HBV is younger and has a lower prevalence of metabolic co-morbidities and a higher frequency of chronic HBeAg infection. Despite having access to care and an indication for treatment, some do not get adequately treated due to several factors including local adaptation that precludes access to treatment.