| 1. |
- Donati, Benedetta, et al.
(författare)
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The rs2294918 E434K variant modulates PNPLA3 expression and liver damage.
- 2016
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Ingår i: Hepatology (Baltimore, Md.). - : Ovid Technologies (Wolters Kluwer Health). - 1527-3350 .- 0270-9139. ; 63:3, s. 787-798
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Tidskriftsartikel (refereegranskat)abstract
- The PNPLA3 rs738409 polymorphism (I148M) is a major determinant of hepatic fat and predisposes to the full spectrum of liver damage in nonalcoholic fatty liver disease (NAFLD). Aim of this study was to evaluate whether additional PNPLA3 coding variants contribute to NAFLD susceptibility, first in individuals with contrasting phenotypes (with early onset NAFLD vs. very low aminotransferases), and then in a large validation cohort. Rare PNPLA3 variants were not detected by sequencing coding regions and intron-exon boundaries either in 142 patients with early-onset NAFLD, nor in 100 healthy individuals with ALT <22/20 IU/ml. Besides rs738409 I148M, the rs2294918 G>A polymorphism (E434K sequence variant) was over-represented in NAFLD (adjusted p=0.01). In 1447 subjects with and without NAFLD, the 148M-434E (p<0.0001), but not the 148M-434K haplotype (p>0.9), was associated with histological NAFLD and steatohepatitis. Both the I148M (p=0.0002) and E434K variants (p=0.044) were associated with serum ALT levels, by interacting each other, in that the 434K hampered the association with liver damage of the 148M allele (p=0.006). The E434K variant did not affect PNPLA3 enzymatic activity, but carriers of the rs2294918 A allele (434K) displayed lower hepatic PNPLA3 mRNA and protein levels (p<0.05).
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| 2. |
- Dongiovanni, Paola, et al.
(författare)
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PCSK7 gene variation bridges atherogenic dyslipidemia with hepatic inflammation in NAFLD patients.
- 2019
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Ingår i: Journal of lipid research. - 1539-7262. ; 60:June, s. 1144-1153
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Tidskriftsartikel (refereegranskat)abstract
- Dyslipidemia and altered iron metabolism are typical features of non-alcoholic fatty liver disease (NAFLD). Proprotein Convertase Subtilisin/Kexin Type 7 (PCSK7) gene variation has been associated with circulating lipids and liver damage during iron overload. Aim of this study was to examine the impact of the PCSK7 rs236918 variant on NAFLD-related traits in 1,801 individuals from the Liver Biopsy Cohort (LBC), 500,000 from the UK Biobank Cohort (UKBBC), and 4,580 from the Dallas Heart Study (DHS). The minor PCSK7 rs236918 C allele was associated with higher triglycerides, aminotransferases and hepatic inflammation in the LBC (p<0.05) and with hypercholesterolemia and liver disease in the UKBBC. In the DHS, PCSK7 missense variants were associated with circulating lipids. PCSK7 was expressed in hepatocytes and its hepatic expression correlated with that of lipogenic genes (p<0.05). The rs236918 C allele was associated with upregulation of a new 'intra-PCSK7' lnc-RNA predicted to interact with the protein, higher hepatic and circulating PCSK7 protein (p<0.01), and the latter correlated with triglycerides (p=0.04). In HepG2, PCSK7 deletion reduced lipogenesis, fat accumulation, inflammation, TGFB pathway activation and fibrogenesis. In conclusion, PCSK7 gene variation is associated with dyslipidemia and more severe liver disease in high risk individuals, likely by modulating PCSK7 expression/activity.
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| 3. |
- Dongiovanni, Paola, et al.
(författare)
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Statin use and nonalcoholic steatohepatitis in at risk individuals.
- 2015
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Ingår i: Journal of hepatology. - : Elsevier BV. - 1600-0641 .- 0168-8278. ; 63:3, s. 705-712
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Tidskriftsartikel (refereegranskat)abstract
- Excess hepatic free cholesterol contributes to the pathogenesis of nonalcoholic steatohepatitis, and statins reduce cholesterol synthesis. Aim of this study was to assess whether statin use is associated with histological liver damage related to steatohepatitis.
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| 4. |
- Mancina, Rosellina Margherita, et al.
(författare)
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The MBOAT7-TMC4 Variant rs641738 Increases Risk of Nonalcoholic Fatty Liver Disease in Individuals of European Descent.
- 2016
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Ingår i: Gastroenterology. - : Elsevier BV. - 1528-0012 .- 0016-5085. ; 150:5, s. 1219-1230
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Tidskriftsartikel (refereegranskat)abstract
- Nonalcoholic fatty liver disease (NAFLD) is a leading cause of liver damage and is characterized by steatosis. Genetic factors increase risk for progressive NAFLD. A genome-wide association study showed that the rs641738 C>T variant in the locus that contains the membrane bound O-acyltransferase domain-containing 7 gene (MBOAT7, also called LPIAT1) and transmembrane channel-like 4 gene (TMC4) increased the risk for cirrhosis in alcohol abusers. We investigated whether the MBOAT7-TMC4 is a susceptibility locus for the development and progression of NAFLD.
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| 5. |
- Nobili, Valerio, et al.
(författare)
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Tyrosinemia type 1: metastatic hepatoblastoma with a favorable outcome.
- 2010
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Ingår i: Pediatrics. - : American Academy of Pediatrics (AAP). - 1098-4275 .- 0031-4005. ; 126:1
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Tidskriftsartikel (refereegranskat)abstract
- The clinical course of tyrosinemia type 1 is characterized by acute liver failure in infancy or chronic liver dysfunction and renal Fanconi syndrome in late-presenting cases. Dietary treatment may improve liver function but does not prevent the development of hepatocellular carcinoma (HCC) in late childhood. A new treatment strategy that uses 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), which prevents the production of toxic/carcinogenic metabolites, has dramatically changed the outcome of the disease by reducing the occurrence of liver cancer, especially in patients who start this treatment before the age of 2 years. We report here the case of a patient with a diagnosis of tyrosinemia type 1 at 5 months of age who was treated with NTBC and dietary restriction and in whom a liver neoplasm with lung metastases, histologically determined to be HCC, was found at the age of 15 months. A conservative approach that consisted of chemotherapy and partial hepatectomy resulted in a 12-year disease-free period. The excellent postchemotherapy course, in sharp contrast to the expected course of HCC, led to histologic reevaluation with reclassification of the neoplasm as hepatoblastoma. A diagnosis of hepatoblastoma would no longer be a mandate for a liver transplant for patients with tyrosinemia type 1 undergoing NTBC treatment. We encourage clinicians to perform more accurate evaluation of liver histology, because a neoplastic mass in a child with tyrosinemia type 1 is not the same as HCC.
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