A metabolic associated fatty liver disease risk variant in MBOAT7 regulates toll like receptor induced outcomes

Alharthi, Jawaher; Bayoumi, Ali; Thabet, Khaled; Pan, Ziyan; Gloss, Brian; Latchoumanin, Olivier; Lundberg, Mischa; Twine, Natalie A.; McLeod, Duncan; Alenizi, Shafi; Adams, Leon A.; Weltman, Martin; Berg, Thomas; Liddle, Christopher; George, Jacob; Eslam, Mohammed

doi:10.1038/s41467-022-35158-9

Cited by 21 publications

(21 citation statements)

References 73 publications

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“…These alterations are associated with a redistribution of AA toward proinflammatory eicosanoids, induction of endoplasmic reticulum stress, mitochondrial dysfunction, and remodelling of the accessible inflammatory‐related chromatin landscape culminating in macrophage inflammatory responses to TLRs. Activation of MBOAT7 reverses these effects 106 …”

Section: Mboat7 Involvement In Extrahepatic Diseasesmentioning

confidence: 96%

“…Activation of MBOAT7 reverses these effects. 106 Recently, the presence of the MBOAT7 rs641738 C>T variant was linked to a more severe liver injury during hospitalization for COVID-19. Carriers of the MBOAT7 rs641738 C>T variant displayed more severe liver injury characterized by increased ALP, GGT, ALT, and bilirubin and decreased albumin levels during hospitalization for COVID-19, as compared to wild type.…”

Section: Mboat7 and Covid-19mentioning

confidence: 99%

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MBOAT7 in liver and extrahepatic diseases

Caddeo,

Spagnuolo,

Maurotti

2023

Liver International

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MBOAT7 is a protein anchored to endomembranes by several transmembrane domains. It has a catalytic dyad involved in remodelling of phosphatidylinositol with polyunsaturated fatty acids. Genetic variants in the MBOAT7 gene have been associated with the entire spectrum of non‐alcoholic fatty liver (NAFLD), recently redefined as metabolic dysfunction‐associated fatty liver disease (MAFLD) and, lately, steatotic liver disease (SLD), and to an increasing number of extrahepatic conditions. In this review, we will (a) elucidate the molecular mechanisms by which MBOAT7 loss‐of‐function predisposes to MAFLD and neurodevelopmental disorders and (b) discuss the growing number of genetic studies linking MBOAT7 to hepatic and extrahepatic diseases. MBOAT7 complete loss of function causes severe changes in brain development resulting in several neurological manifestations. Lower MBOAT7 hepatic expression at both the mRNA and protein levels, due to missense nucleotide polymorphisms (SNPs) in the locus containing the MBOAT7 gene, affects specifically metabolic and viral diseases in the liver from simple steatosis to hepatocellular carcinoma, and potentially COVID‐19 disease. This body of evidence shows that phosphatidylinositol remodelling is a key factor for human health.

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Section: Mboat7 Involvement In Extrahepatic Diseasesmentioning

confidence: 96%

Section: Mboat7 and Covid-19mentioning

confidence: 99%

MBOAT7 in liver and extrahepatic diseases

Caddeo,

Spagnuolo,

Maurotti

2023

Liver International

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“…It is important to note during the preparation of this manuscript, an independent study discovered a potential role for MBOAT7 in suppressing toll-like receptor (TLR) signaling and pro-inflammatory cytokine production in macrophages and Kupffer cells in the context of non-alcoholic fatty liver disease (NAFLD) (Alharthi et al, 2022). Furthermore, early studies examining the expression and substrate specificity for diverse lysophospholipid acyltransferases showed that MBOAT7-driven PI remodeling was highly active in human neutrophils where it can modulate the production of pro-inflammatory arachidonic acid-derived lipid mediators (Gijón et al, 2008).…”

Section: Resultsmentioning

confidence: 99%

Membrane Bound O-Acyltransferase 7 (MBOAT7) Shapes Lysosomal Lipid Homeostasis and Function to Control Alcohol-Associated Liver Injury

Varadharajan,

Ramachandiran,

Massey

et al. 2023

Preprint

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Several recent genome-wide association studies (GWAS) have identified single nucleotide polymorphism (SNPs) near the gene encoding membrane-boundO-acyltransferase 7 (MBOAT7) that is associated with advanced liver diseases. In fact, a commonMBOAT7variant (rs641738), which is associated with reducedMBOAT7expression, confers increased susceptibility to non-alcoholic fatty liver disease (NAFLD), alcohol-associated liver disease (ALD), and liver fibrosis in those chronically infected with hepatitis viruses B and C. TheMBOAT7gene encodes a lysophosphatidylinositol (LPI) acyltransferase enzyme that produces the most abundant form of phosphatidylinositol 38:4 (PI 18:0/20:4). Although these recent genetic studies clearly implicate MBOAT7 function in liver disease progression, the mechanism(s) by which MBOAT7-driven LPI acylation regulates liver disease is currently unknown. Previously we showed that antisense oligonucleotide (ASO)-mediated knockdown ofMboat7promoted nonalcoholic fatty liver disease (NAFLD) in mice (Helsley et al., 2019). Here, we provide mechanistic insights into howMBOAT7loss of function promotes alcohol-associated liver disease (ALD). In agreement with GWAS studies, we find that circulating levels of metabolic product of MBOAT7 (PI 38:4) are significantly reduced in heavy drinkers compared to age-matched healthy controls. Hepatocyte specific genetic deletion (Mboat7HSKO), but not myeloid-specific deletion (Mboat7MSKO), ofMboat7in mice results in enhanced ethanol-induced hepatic steatosis and high concentrations of plasma alanine aminotransferase (ALT). Given MBOAT7 is a lipid metabolic enzyme, we performed comprehensive lipidomic profiling of the liver and identified a striking reorganization of the hepatic lipidome upon ethanol feeding inMboat7HSKOmice. Specifically, we observed large increases in the levels of endosomal/lysosomal lipids including bis(monoacylglycero)phosphates (BMP) and phosphatidylglycerols (PGs) in ethanol-exposedMboat7HSKOmice. In parallel, ethanol-fedMboat7HSKOmice exhibited marked dysregulation of autophagic flux and lysosomal biogenesis when exposed to ethanol. This was associated with impaired transcription factor EB (TFEB)-mediated lysosomal biogenesis and accumulation of autophagosomes. Collectively, this works provides new molecular insights into how genetic variation inMBOAT7impacts ALD progression in humans and mice. This work is the first to causally link MBOAT7 loss of function in hepatocytes, but not myeloid cells, to ethanol-induced liver injury via dysregulation of lysosomal biogenesis and autophagic flux.

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“…Certain genetic causes are involved in the etiology of MAFLD. Studies have shown that the breakdown of toll-like receptor (TLR) tolerance can lead to tissue damage and the activation of TLR causes inappropriate inflammatory reactions that have been implicated in the severity of MAFLD [ 19 ]. Studies has now focused on genome-wide association studies (GWAS) to discover via multi-trait GWAS, genome-wide association studies (PheWAS), Mendelian randomization and functional annotation studies [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

Fibrosis score 4 index has an independent relationship with coronary artery diseases in patients with metabolic-associated fatty liver disease

Namakchian

Rabizadeh

Seifouri

et al. 2023

Diabetol Metab Syndr

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Background Metabolic-associated fatty liver disease (MAFLD), one of the most common liver diseases, is detected in patients with concomitant hepatic steatosis and Type 2 Diabetes (T2D). We looked into the relationship between Fibrosis-4 (FIB-4) index and coronary artery diseases (CAD) in patients with MAFLD, to further look into the efficiency of FIB-4 in screening for CAD among patients with MAFLD. Method In this study, we included 1664 patients with MAFLD (T2D, who also had hepatic steatosis) during 2012–2022 and divided them into 2 groups; CAD and non-CAD. Demographic, Anthropometric indices, liver function tests, lipid profile and FIB-4 index of all patients were evaluated and compared. Result Among the 1644 patients (all have MAFLD), 364(21.4%) had CAD. Patients with MAFLD and CAD were more probable to be hypertensive, have longer duration of diabetes and be older (with p-values < 0.001). After adjustment for confounding factors, in a multivariable logistic regression model, FIB4 showed a significant independent relationship with concomitant MAFLD and CAD. Upper Tertile FIB-4 had an odds ratio of 3.28 (P-value = 0.002) to predict CAD. Furthermore, in Receiver Operating Characteristic (ROC) Curve analysis with the maximum Youden Index, a FIB-4 cut-off of 0.85 (AUC = 0.656, 95% CI 0.618–0.693, P < 0.001) noted to predict CAD in patients with MAFLD. Conclusion This study showed that the FIB-4 score independently correlates with CAD in patients with MAFLD.

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A metabolic associated fatty liver disease risk variant in MBOAT7 regulates toll like receptor induced outcomes

Cited by 21 publications

References 73 publications

MBOAT7 in liver and extrahepatic diseases

MBOAT7 in liver and extrahepatic diseases

Membrane Bound O-Acyltransferase 7 (MBOAT7) Shapes Lysosomal Lipid Homeostasis and Function to Control Alcohol-Associated Liver Injury

Fibrosis score 4 index has an independent relationship with coronary artery diseases in patients with metabolic-associated fatty liver disease

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