| 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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Protein phosphatase 1 regulatory subunit 3B gene variation protects against hepatic fat accumulation and fibrosis in individuals at high risk of nonalcoholic fatty liver disease.
- 2018
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Ingår i: Hepatology communications. - : Ovid Technologies (Wolters Kluwer Health). - 2471-254X. ; 2:6, s. 666-675
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Tidskriftsartikel (refereegranskat)abstract
- Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver damage and has a strong genetic component. The rs4841132 G>A variant, modulating the expression of protein phosphatase 1 regulatory subunit 3B (PPP1R3B), which is involved in glycogen synthesis, has been reported to reduce the risk of NAFLD but at the same time may favor liver disease by facilitating glycogen accumulation. The aim of this study was to assess the impact of rs4841132 on development of histologic steatosis and fibrosis in 1,388 European individuals in a liver biopsy cohort, on NAFLD hepatocellular carcinoma in a cross-sectional Italian cohort (n = 132 cases), and on liver disease at the population level in the United Kingdom Biobank cohort. We investigated the underlying mechanism by examining the impact of the variant on gene expression profiles. In the liver biopsy cohort, the rs4841132 minor A allele was associated with protection against steatosis (odds ratio [OR], 0.63; 95% confidence interval [CI], 0.42-0.95; P = 0.03) and clinically significant fibrosis (OR, 0.35; 95% CI, 0.14-0.87; P = 0.02) and with reduced circulating cholesterol (P = 0.02). This translated into protection against hepatocellular carcinoma development (OR, 0.22; 95% CI, 0.07-0.70; P = 0.01). At the population level, the rs4841132 variation was not associated with nonalcoholic or nonviral diseases of the liver but was associated with lower cholesterol (P = 1.7 × 10-8). In individuals with obesity, the A allele protecting against steatosis was associated with increased PPP1R3B messenger RNA expression and activation of lipid oxidation and with down-regulation of pathways related to lipid metabolism, inflammation, and cell cycle. Conclusion: The rs4841132 A allele is associated with protection against hepatic steatosis and fibrosis in individuals at high risk of NAFLD but not in the general population and against dyslipidemia. The mechanism may be related to modulation of PPP1R3B expression and hepatic lipid metabolism. (Hepatology Communications 2018;2:666-675).
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| 4. |
- 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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| 5. |
- 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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| 6. |
- Meroni, Marica, et al.
(författare)
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Mboat7 down-regulation by hyper-insulinemia induces fat accumulation in hepatocytes.
- 2020
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Ingår i: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 52
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Tidskriftsartikel (refereegranskat)abstract
- Naturally occurring variation in Membrane-bound O-acyltransferase domain-containing 7 (MBOAT7), encoding for an enzyme involved in phosphatidylinositol acyl-chain remodelling, has been associated with fatty liver and hepatic disorders. Here, we examined the relationship between hepatic Mboat7 down-regulation and fat accumulation.Hepatic MBOAT7 expression was surveyed in 119 obese individuals and in experimental models. MBOAT7 was acutely silenced by antisense oligonucleotides in C57Bl/6 mice, and by CRISPR/Cas9 in HepG2 hepatocytes.In obese individuals, hepatic MBOAT7 mRNA decreased from normal liver to steatohepatitis, independently of diabetes, inflammation and MBOAT7 genotype. Hepatic MBOAT7 levels were reduced in murine models of fatty liver, and by hyper-insulinemia. In wild-type mice, Mboat7 was down-regulated by refeeding and insulin, concomitantly with insulin signalling activation. Acute hepatic Mboat7 silencing promoted hepatic steatosis in vivo and enhanced expression of fatty acid transporter Fatp1. MBOAT7 deletion in hepatocytes reduced the incorporation of arachidonic acid into phosphatidylinositol, consistently with decreased enzymatic activity, determining the accumulation of saturated triglycerides, enhanced lipogenesis and FATP1 expression, while FATP1 deletion rescued the phenotype.MBOAT7 down-regulation by hyper-insulinemia contributes to hepatic fat accumulation, impairing phosphatidylinositol remodelling and up-regulating FATP1.LV was supported by MyFirst Grant AIRC n.16888, Ricerca Finalizzata Ministero della Salute RF-2016-02,364,358, Ricerca corrente Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico; LV and AG received funding from the European Union Programme Horizon 2020 (No. 777,377) for the project LITMUS-"Liver Investigation: Testing Marker Utility in Steatohepatitis". MM was supported by Fondazione Italiana per lo Studio del Fegato (AISF) 'Mario Coppo' fellowship.
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| 7. |
- Stefania, Grimaudo, et al.
(författare)
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PCSK9 rs11591147 R46L Loss-of-Function Variant Protects Against Liver Damage in Individuals with NAFLD.
- 2021
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Ingår i: Liver international : official journal of the International Association for the Study of the Liver. - : Wiley. - 1478-3231. ; 41:2, s. 321-332
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Tidskriftsartikel (refereegranskat)abstract
- The proproteinconvertasesubtilisin/kexin type 9(PCSK9) plays a key role in cholesterol homeostasis, and its inhibition represents an effective therapy to lower LDL-C levels. In this study, we examined the impact of the PCSK9 rs11591147 loss-of-function (LOF) variant on liver damage in a multicenter collection of patients at risk of nonalcoholic steatohepatitis (NASH), in clinical samples and experimental models.We considered 1,874 consecutive individuals at risk of NASH as determined by histology. The SNP rs11591147, encoding for the p.R46L variant of PCSK9,was genotyped by TaqMan assays. We also evaluated 1)PCSK9 mRNA hepatic expression in human liver, and 2)the impact of a NASH-inducing diet in mice with hepatic overexpression of human PCSK9.Carriers of PCSK9 rs11591147 had lower circulating LDL-C levels and were protected against NAFLD (OR0.42; 95%C.I0.22-0.81; P=0.01), NASH (OR0.48;95%C.I.0.26-0.87;P=0.01)and more severe fibrosis (OR0.55; 95%C.I.0.32-0.94; P=0.03) independently of clinical, metabolic and genetic confounding factors. PCSK9 hepatic expression was directly correlated with liver steatosis(P=0.03). Finally, liver-specific overexpression of human PCSK9 in male mice drives NAFLD and fibrosis upon a dietary challenge.In individuals at risk of NASH, PCSK9 was induced with hepatic fat accumulation and PCSK9 rs11591147 LOF variant was protective against liver steatosis, NASH and fibrosis, suggesting PCSK9 inhibition may be a new therapeutic strategy to treat NASH.
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