MBOAT7 down-regulation by genetic and environmental factors predisposes to MAFLD - PubMed (original) (raw)

Review

MBOAT7 down-regulation by genetic and environmental factors predisposes to MAFLD

Marica Meroni et al. EBioMedicine. 2020 Jul.

Abstract

Metabolic associated fatty liver disease (MAFLD) encompasses a broad spectrum of hepatic disorders, which include steatosis, nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis, that is a critical risk factor for hepatocellular carcinoma (HCC) development. Its pathogenesis is intertwined with obesity and type 2 diabetes (T2D). However, the predisposition to develop MAFLD is severely influenced by environmental and inherited cues. The rs641738 variant close to MBOAT7 gene has been identified by a genome-wide association screening in heavy drinkers. Although this variant has been associated with the entire spectrum of MAFLD, these results have not been completely replicated and the debate is still opened. Thus, functional studies that unravel the biological mechanisms underlying the genetic association with fatty liver are required. This review aims to summarize the clinical and experimental findings regarding the rs641738 variation and MBOAT7 function, with the purpose to shed light to its role as novel player in MAFLD pathophysiology.

Keywords: Hyperinsulinemia; Insulin resistance; LPIAT1; MAFLD; MBOAT7; NASH; Phospholipids.

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Conflict of interest statement

Declaration of Competing Interest The authors declare no conflict of interest.

Figures

Fig. 1

Phosphatidylcholines (PC), Phosphatidylserine (PS), Phosphatidylethanolamines (PE) and Phosphatidylinositols (PI) are the main components of the membranes. Phospholipase A2 (cPLA2) releases free arachidonic acid from the sn-2 position of phospholipids, generating the corresponding lysophospholipids and free arachidonic acid. The free arachidonic acid produced may become the precursor of proinflammatory mediators (Eicosanoids) or it may be returned to the phospholipid pool through the activation of an acyl-CoA ligase and either MBOAT7 (that uses lyso-PI) or MBOAT5 (that uses lyso-PC, lyso-PS, and lyso-PE). Thimerosal, an MBOAT unspecific inhibitor, increases the production of Eicosanoids (Prostaglandins and Leukotrienes). Modified by Gijon et al. .

Fig. 2

During fasting or in rs641738 C allele carriers (left panel), MBOAT7 is highly expressed and it localizes into the membranes, where it conjugates arachidonoyl-CoA to the second acyl-chain of Lyso-PI, thus guaranteeing their physiological fluidity and the dynamism, that allows the exchange of the metabolites from the membranes to intracellular compartments. During hyperinsulinemia or in carriers of the T risk allele (right panel), MBOAT7 is reduced, favoring the increase of saturated PI, which are accumulated and delivered to TAG synthesis. This process requires the up-regulation of FATP1 and associates in vitro with enhanced de novo lipogenesis. Modified from Meroni et al., .

Fig. 3

Unhealthy dietary habits, excessive caloric intake, high fructose consumption and poor physical exercise are widely recognized as risk factors of IR development. During diet-induced or pathological hyperinsulinemia, MBOAT7 is hampered in intestine, adipose tissue and in liver. In adipose tissue, peripheral IR, induces MBOAT7 down-regulation and lipolysis, favoring an exaggerated free fatty acid (FFA) release into the bloodstream. As a consequence, FFAs uptake increases in hepatocytes, even due to the up-regulation of the fatty acid transporter FATP1. Then, FFAs are stored in intracellular lipid droplets as triglycerides (TAG). Moreover, high insulin concentrations hamper hepatic gene and protein expression of MBOAT7, determining changes in PI composition pattern, favoring in turn, TAG synthesis and de novo lipogenesis. These events may precipitate hepatic fat deposition and fatty liver onset. In turn, MBOAT7 down-regulation per se may be causally implicated in fatty liver and in IR exasperation. The impairment in MBOAT7 function may also facilitate the switch from simple steatosis to steatohepatitis and fibrosis, affecting lipid composition of the membranes of inflammatory cells and altering lipid mediator profiles. Thus, the increase amount of free arachidonic acid and its conversion in pro-inflammatory mediators triggers immune cell activation. Cytokine release and hyperinsulinemia may then stimulate HSCs to produce ECM, perpetuating fibrogenic processes.

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MBOAT7 down-regulation by genetic and environmental factors predisposes to MAFLD - PubMed (original) (raw)