TM6SF2 and MBOAT7 Gene Variants in Liver Fibrosis and Cirrhosis

Basytė-Bacevičė, Viktorija; Skiecevičienė, Jurgita; Valantienė, Irena; Šumskienė, Jolanta; Petrenkienė, Vitalija; Kondrackienė, Jūratė; Petrauskas, Dalius; Lammert, Frank; Kupčinskas, Juozas

doi:10.3390/ijms20061277

Cited by 42 publications

(40 citation statements)

References 30 publications

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“…Genome-wide association studies (GWAS) have identified the relationship between PNPLA3, TM6SF2, MBOAT7 single nucleotide polymorphisms (SNPs) and increased risk for chronic liver disease [12]. In previous studies, we found a significant association between PNPLA3 rs738409 and chronic liver injury in our cohort, although no significant associations between TM6SF2 and MBOAT7 variants were observed [13,14].…”

Section: Introductionmentioning

confidence: 42%

SERPINA1 and HSD17B13 Gene Variants in Patients with Liver Fibrosis and Cirrhosis

Basytė-Bacevičė

Skiecevičienė

Valantienė

et al. 2019

JGLD

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Background & Aims: Two single nucleotide polymorphisms (SNPs) in SERPINA1 (Pi*Z rs28929474 and Pi*Srs17580) are risk factors for developing liver cirrhosis. A recent study identified a common SNP in HSD17B13(rs72613567) that conferred protection from chronic liver disease. The aim of the present study was to testthese associations in a cohort of Lithuanian patients with liver fibrosis or cirrhosis. Methods: The study included 302 patients with cirrhosis, 127 patients with liver fibrosis (METAVIR stagesI-III) and 548 controls, all from Lithuania. SNPs were genotyped by quantitative PCR, using TaqMan allelicdiscrimination assays. Adjusted p value of ≤ 0.016 was considered significant. Results: Genotype distributions of SERPINA1 and HSD17B13 SNPs were in Hardy-Weinberg equilibrium.SERPINA1 Pi*Z was not associated with liver fibrosis or cirrhosis. HSD17B13 rs10433937 (in high linkagedisequilibrium with rs72613567; r 2 =0.96) also showed no overall association with liver disease, but the GG-genotype was associated with reduced risk of liver fibrosis (aOR 0.37, p=0.03). SERPINA1 Pi*S was associatedwith higher risk of developing hepatic fibrosis (aOR 3.42, p=0.001) and cirrhosis (aOR 2.59, p=0.02). Conclusions: We found that SERPINA1 Pi*S variant conferred an increased risk of developing liver fibrosis,while SERPINA1 Pi*Z and HSD17B13 rs10433937 were not associated with liver fibrosis or cirrhosis ofdifferent aetiology.

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Section: Introductionmentioning

confidence: 42%

SERPINA1 and HSD17B13 Gene Variants in Patients with Liver Fibrosis and Cirrhosis

Basytė-Bacevičė

Skiecevičienė

Valantienė

et al. 2019

JGLD

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“…2 5 NAFLD has also a strong genetic susceptibility, and among the genes of susceptibility 6 the single nucleotide polymorphism (rs641738 C>T) in the membrane bound O-acyltransferase domain-containing 7 (MBOAT7) gene increases the susceptibility to the entire spectrum of NAFLD, 7 8 by inducing a reduction in the liver MBOAT7 mRNA expression. [8][9][10][11] MBOAT7 encodes lysophosphatidylinositol acyltransferase 1 (LPIAT1), which preferentially incorporates arachidonic acid (AA; 20:4 n-6) into phosphatidylinositol (PI). [12][13][14] PI is a constitutive of membrane phospholipids and the precursor of signalling lipid phosphoinositides, 15 but so far no direct role of PI in TG synthesis has been shown.…”

Section: How Might It Impact On Clinical Practice In the Foreseeable mentioning

confidence: 99%

LPIAT1/MBOAT7 depletion increases triglyceride synthesis fueled by high phosphatidylinositol turnover

Tanaka

Shimanaka

Caddeo

et al. 2020

Gut

107

109

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ObjectiveNon-alcoholic fatty liver disease (NAFLD) is a common prelude to cirrhosis and hepatocellular carcinoma. The genetic rs641738 C>T variant in the lysophosphatidylinositol acyltransferase 1 (LPIAT1)/membrane bound O-acyltransferase domain-containing 7, which incorporates arachidonic acid into phosphatidylinositol (PI), is associated with the entire spectrum of NAFLD. In this study, we investigated the mechanism underlying this association in mice and cultured human hepatocytes.DesignWe generated the hepatocyte-specific Lpiat1 knockout mice to investigate the function of Lpiat1 in vivo. We also depleted LPIAT1 in cultured human hepatic cells using CRISPR-Cas9 systems or siRNA. The effect of LPIAT1-depletion on liver fibrosis was examined in mice fed high fat diet and in liver spheroids. Lipid species were measured using liquid chromatography-electrospray ionisation mass spectrometry. Lipid metabolism was analysed using radiolabeled glycerol or fatty acids.ResultsThe hepatocyte-specific Lpiat1 knockout mice developed hepatic steatosis spontaneously, and hepatic fibrosis on high fat diet feeding. Depletion of LPIAT1 in cultured hepatic cells and in spheroids caused triglyceride accumulation and collagen deposition. The increase in hepatocyte fat content was due to a higher triglyceride synthesis fueled by a non-canonical pathway. Indeed, reduction in the PI acyl chain remodelling caused a high PI turnover, by stimulating at the same time PI synthesis and breakdown. The degradation of PI was mediated by a phospholipase C, which produces diacylglycerol, a precursor of triglyceride.ConclusionWe found a novel pathway fueling triglyceride synthesis in hepatocytes, by a direct metabolic flow of PI into triglycerides. Our findings provide an insight into the pathogenesis and therapeutics of NAFLD.

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“…Genetic testing for risk alleles were in line with known distribution of disease severity 32 , 46 – 48 , but relative risk was too low to suggest a meaningful diagnostic benefit.…”

Section: Discussionmentioning

confidence: 99%

Current NAFLD guidelines for risk stratification in diabetic patients have poor diagnostic discrimination

Blank

Petroff

Beer

et al. 2020

Sci Rep

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Patients with type 2 diabetes (T2D) are at risk for non-alcoholic fatty liver disease (NAFLD) and associated complications. This study evaluated the performance of international (EASL-EASD-EASO) and national (DGVS) guidelines for NAFLD risk stratification. Patients with T2D prospectively underwent ultrasound, liver stiffness measurement (LSM) and serum-based fibrosis markers. Guideline-based risk classification and referral rates for different screening approaches were compared and the diagnostic properties of simplified algorithms, genetic markers and a new NASH surrogate (FAST score) were evaluated. NAFLD risk was present in 184 of 204 screened patients (age 64.2 ± 10.7 years; BMI 32.6 ± 7.6 kg/m2). EASL-EASD-EASO recommended specialist referral for 60–77% depending on the fibrosis score used, only 6% were classified as low risk. The DGVS algorithm required LSM for 76%; 25% were referred for specialised care. The sensitivities of the diagnostic pathways were 47–96%. A simplified referral strategy revealed a sensitivity/specificity of 46/88% for fibrosis risk. Application of the FAST score reduced the referral rate to 35%. This study (a) underlines the high prevalence of fibrosis risk in T2D, (b) demonstrates very high referral rates for in-depth hepatological work-up, and (c) indicates that simpler referral algorithms may produce comparably good results and could facilitate NAFLD screening.

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TM6SF2 and MBOAT7 Gene Variants in Liver Fibrosis and Cirrhosis

Cited by 42 publications

References 30 publications

SERPINA1 and HSD17B13 Gene Variants in Patients with Liver Fibrosis and Cirrhosis

SERPINA1 and HSD17B13 Gene Variants in Patients with Liver Fibrosis and Cirrhosis

LPIAT1/MBOAT7 depletion increases triglyceride synthesis fueled by high phosphatidylinositol turnover

Current NAFLD guidelines for risk stratification in diabetic patients have poor diagnostic discrimination

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