MBOAT7 in liver and extrahepatic diseases

Abstract

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.

IL32 downregulation lowers triglycerides and type I collagen in di-lineage human primary liver organoids

“…We have previously shown that changes in the hepatic PI remodeling due to lower expression of MBOAT7 increases liver triglyceride content. 44 , 45 The results of this work reinforce the notion of a role of PI in intrahepatic triglycerides homeostasis.…”

Exploring the impact of lipid droplets on the evolution and progress of hepatocarcinoma

“…MASLD cohort studies have found a substantial relationship between the RS641738T mutation in MBOAT7 and increased hepatic fat and fibrosis, which results in lower liver protein levels ( Luukkonen et al, 2016a ). These associations were verified by a comprehensive meta-analysis including more than a million people, which additionally linked them to decrease serum TGs and increase blood alanine aminotransferase levels ( Teo et al, 2021 ; Caddeo et al, 2023 ). Moreover, MBOAT7 liver expression was found to be significantly lower in both human and mouse obesity models, implicating it in the etiology of MASLD ( Helsley et al, 2019 ).…”

The Pivotal Role of the Membrane-Bound O-Acyltransferase Domain Containing 7 in Non-Alcoholic Fatty Liver Disease

“…Recent studies have identified several genetic susceptibility variants comprising of single-nucleotide polymorphisms in PNPLA3 (rs738409), TM6SF2 (rs8542926), and LX-PLAL1 (rs12137855) [6]. The contributions of the PNPLA3 polymorphism in NAFLD have been widely studied, while in contrast, the molecular biochemical mechanistic insights underlying the MBOAT7 polymorphism are little understood [6].…”

“…Recent studies have identified several genetic susceptibility variants comprising of single-nucleotide polymorphisms in PNPLA3 (rs738409), TM6SF2 (rs8542926), and LX-PLAL1 (rs12137855) [6]. The contributions of the PNPLA3 polymorphism in NAFLD have been widely studied, while in contrast, the molecular biochemical mechanistic insights underlying the MBOAT7 polymorphism are little understood [6]. Recently, the identification of genetic variant rs641738 near two genes encoding the MBOAT7 gene and transmembrane channel-like 4 (TMC4) in determining the risk of NAFLD and its complications has gained utmost importance and still needs further exploration for a targeted drug design to treat complex NAFLD [7].…”