RESUMEN
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.
Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Animales , Humanos , Ratones , Modelos Animales de Enfermedad , Fibrosis , Glucosa/metabolismo , Glucógeno/metabolismo , Hepatocitos/metabolismo , Hígado/metabolismo , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Succinatos/metabolismo , Succinatos/farmacologíaRESUMEN
Chronic hepatitis C virus infection is usually asymptomatic. The severity of the hepatic lesion in these patients at diagnosis varies and, from the histopathologic point of view, most have mild disease. A series of factors have been described that correlate with the progression of fibrosis in patients with mild fibrosis: age at diagnosis, the duration of the infection, male sex, HIV coinfection, transaminase levels during follow-up, alcohol consumption, metabolic factors such as diabetes and overweight, necroinflammatory activity in the initial biopsy, and the degree of steatosis. In patients with genotype 1 hepatitis C infection, the standard treatment has been pegylated interferon and ribavirin. However, response rates are markedly increased by concomitant use of first-generation protease inhibitors, boceprevir or telaprevir. In patients with moderate fibrosis, these drugs are well tolerated, in addition to being effective. Currently, dual therapy should be reserved for patients with good baseline predictive factors of response and/or contraindications for treatment with telaprevir or boceprevir. In patients with genotypes other than genotype 1, the standard treatment continues to be the combination of pegylated interferon and ribavirin, although the development of new direct-acting antiviral agents such as sofosbuvir and simeprevir will change the strategies used in these patients. The decision to wait for the new treatments is complex because their release date is unknown; likewise, their high cost will limit the possibilities for their use.
Asunto(s)
Hepatitis C Crónica , Antivirales/efectos adversos , Antivirales/uso terapéutico , Enfermedades Asintomáticas , Ensayos Clínicos como Asunto , Comorbilidad , Progresión de la Enfermedad , Quimioterapia Combinada , Femenino , Genotipo , Infecciones por VIH/epidemiología , Hepacivirus/genética , Hepacivirus/aislamiento & purificación , Hepatitis C Crónica/diagnóstico , Hepatitis C Crónica/epidemiología , Hepatitis C Crónica/terapia , Hepatitis C Crónica/virología , Humanos , Cirrosis Hepática/etiología , Pruebas de Función Hepática , Masculino , Estudios Multicéntricos como Asunto , Inhibidores de Proteasas/efectos adversos , Inhibidores de Proteasas/uso terapéutico , Factores de Riesgo , Terapias en Investigación , Resultado del TratamientoAsunto(s)
Antivirales/uso terapéutico , Hepacivirus/aislamiento & purificación , Hepatitis C Crónica/tratamiento farmacológico , Interferón Tipo I/uso terapéutico , Polietilenglicoles/uso terapéutico , Inhibidores de Proteasas/uso terapéutico , Antivirales/administración & dosificación , Biopsia , Contraindicaciones , Diagnóstico por Imagen/métodos , Quimioterapia Combinada , Genotipo , Accesibilidad a los Servicios de Salud , Hepacivirus/clasificación , Hepacivirus/genética , Hepatitis C Crónica/genética , Hepatitis C Crónica/virología , Humanos , Consentimiento Informado , Interferón Tipo I/administración & dosificación , Interferones , Interleucinas/genética , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/etiología , Cirrosis Hepática/patología , Oligopéptidos/administración & dosificación , Oligopéptidos/uso terapéutico , Grupo de Atención al Paciente , Polietilenglicoles/administración & dosificación , Prolina/administración & dosificación , Prolina/análogos & derivados , Prolina/uso terapéutico , Inhibidores de Proteasas/administración & dosificación , Recurrencia , Ribavirina/administración & dosificación , Ribavirina/uso terapéutico , Carga ViralRESUMEN
BACKGROUND: Although standard dose interferon (IFN) is successful in only 5% of patients with compensated hepatitis C virus (HCV)-related cirrhosis, it has been suggested that this therapy might decrease the risk of complications or the incidence of hepatocellular carcinoma. Based on HCV kinetics, daily IFN may improve response rates. PATIENTS AND METHOD: Forty cirrhotic patients were randomised to receive (Group I: 19) or not (Group II: 21) treatment with IFN (4.5 MU/daily for 24 weeks, followed by 4.5 MU/48 hours for a further 24 weeks period, only if ALT was within normal values). RESULTS: Dose reduction and discontinuation for adverse events was required in 11 (58%) and 6 (31.5%) cases, respectively. End-of-treatment response was not observed in any of the 21 controls but in 4 of the 19 (21%) treated patients (p = 0.04); a sustained response was achieved in only 2 treated patients (10.5%). The 3-year probability of developing any of the following: ascites, hepatocellular carcinoma, transplantation or death was lower in Group I than in Group II (6% vs 27%; p = 0.05). CONCLUSION: Although induction IFN therapy is associated with common side effects and poor sustained response in compensated HCV-related cirrhosis, it might improve the outcome of patients at the medium-term.