Iron in fatty liver and in the metabolic syndrome: A promising therapeutic target

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The SOD2 C47T polymorphism influences NAFLD fibrosis severity: evidence from case-control and intra-familial allele association studies.

AIMS: Non-alcoholic fatty liver disease (NAFLD) is a complex disease trait where genetic variations and environment interact to determine disease progression. The association of PNPLA3 with advanced disease has been consistently demonstrated but many other modifier genes remain unidentified. In NAFLD, increased fatty acid oxidation produces high levels of reactive oxygen species. Manganese-dependent superoxide dismutase (MnSOD), encoded by the SOD2 gene, plays an important role in protecting cells from oxidative stress. A common non-synonymous polymorphism in SOD2 (C47T; rs4880) is associated with decreased MnSOD mitochondrial targeting and activity making it a good candidate modifier of NAFLD severity. METHODS: The relevance of the SOD2 C47T polymorphism to fibrotic NAFLD was assessed by two complementary approaches: we sought preferential transmission of alleles from parents to affected children in 71 family trios and adopted a case-control approach to compare genotype frequencies in a cohort of 502 European NAFLD patients. RESULTS: In the family study, 55 families were informative. The T allele was transmitted on 47/76 (62%) possible occasions whereas the C allele was transmitted on only 29/76 (38%) occasions, p=0.038. In the case control study, the presence of advanced fibrosis (stage>1) increased with the number of T alleles, p=0.008 for trend. Multivariate analysis showed susceptibility to advanced fibrotic disease was determined by SOD2 genotype (OR 1.56 (95% CI 1.09-2.25), p=0.014), PNPLA3 genotype (p=0.041), type 2 diabetes mellitus (p=0.009) and histological severity of NASH (p=2.0×10(-16)). CONCLUSIONS: Carriage of the SOD2 C47T polymorphism is associated with more advanced fibrosis in NASH

Liver transplantation for hepatocellular carcinoma in a patient with a novel telomerase mutation and steatosis

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FGF23 and Fetuin-A Interaction in the Liver and in the Circulation

Recently it has been demonstrated that Fetuin-A, an anti-inflammatory protein synthesized by the liver, is produced also in bone by an FGF23-regulated pathway. FGF23 has been also demonstrated to induce inflammatory cytokine production in the liver. This study aimed to explore if FGF23 plays a role in the Fetuin-A production in the liver cells too and the possible relationships with FGF23 pro-inflammatory effects.FGF23 and Fetuin-A were studied in liver, kidney and in plasma with immunochemistry, immunoprecipitation, western blot, chromatin immunoprecipitation, duolink, ELISA, qrtPCR methodology.FGF23 is produced, but not secreted by the liver cells. In hepatocytes and circulation, FGF23 was present only strictly linked to Fetuin-A, while Fetuin-A was found also in unbounded form. No link was observed in the kidney. FGF23 up to 600 pg/ml stimulates, while, at higher concentrations, reduces Fetuin-A expression.Notably, overall the range of concentrations, FGF23 stimulates Fetuin-A promoter, TNF alpha and IL6 expression.In the nucleus, FGF23 seems to act as a direct transcription factor of Fetuin-A promoter. These results suggest that FGF23 played a direct regulatory role in Fetuin-A expression in liver cells with a biphasic effect: Fetuin-A progressively increases when FGF23 increases up to 400-600 pg/mL, and declines at higher FGF23 concentrations.These results lead us to hypothesize: a) a possible epigenetic post-transcriptional regulation; b) a possible counter-regulatory effect of FGF23 induced inflammatory cytokines (TNF alpha/NF-kappa B mechanism). This study could add an additional key for the interpretation of the possible mechanisms linking FGF23, Fetuin-A and inflammation in CKD patients and suggests a role for FGF23 as transcription factor

Nutritional interventions with bacillus coagulans improved glucose metabolism and hyperinsulinemia in mice with acute intermittent porphyria

Acute intermittent porphyria (AIP) is a metabolic disorder caused by mutations in the porphobilinogen deaminase (PBGD) gene, encoding the third enzyme of the heme synthesis pathway. Although AIP is characterized by low clinical penetrance (~1% of PBGD mutation carriers), patients with clinically stable disease report chronic symptoms and frequently show insulin resistance. This study aimed to evaluate the beneficial impact of nutritional interventions on correct carbohydrate dysfunctions in a mouse model of AIP that reproduces insulin resistance and altered glucose metabolism. The addition of spores of Bacillus coagulans in drinking water for 12 weeks modified the gut microbiome composition in AIP mice, ameliorated glucose tolerance and hyperinsulinemia, and stimulated fat disposal in adipose tissue. Lipid breakdown may be mediated by muscles burning energy and heat dissipation by brown adipose tissue, resulting in a loss of fatty tissue and improved lean/fat tissue ratio. Probiotic supplementation also improved muscle glucose uptake, as measured using Positron Emission Tomography (PET) analysis. In conclusion, these data provide a proof of concept that probiotics, as a dietary intervention in AIP, induce relevant changes in intestinal bacteria composition and improve glucose uptake and muscular energy utilization. Probiotics may offer a safe, efficient, and cost-effective option to manage people with insulin resistance associated with AIP.This research was supported in part by grants from the Spanish Institute of Health Carlos III (FIS) cofunded by the European Union (ERDF/ESF, “A way to make Europe”/“Investing in your future” (grant number PI21/00546) and the Spanish Fundación Mutua Madrileña de Investigación Médica

Rare ATG7 genetic variants predispose patients to severe fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver disorders and has a strong heritable component. The aim of this study was to identify new loci that contribute to severe NAFLD by examining rare variants