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

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          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.

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          A subdomain of the endoplasmic reticulum forms a cradle for autophagosome formation.

          Mitsuko Hayashi-Nishino, Naonobu Fujita, Takeshi Noda … (2009)
          Autophagy is a bulk degradation process in eukaryotic cells and has fundamental roles in cellular homeostasis.The origin and source of autophagosomal membranes are long-standing questions in the field. Using electron microscopy, we show that, in mammalian culture cells, the endoplasmic reticulum (ER) associates with early autophagic structures called isolation membranes (IMs). Overexpression of an Atg4B mutant, which causes defects in autophagosome formation, induces the accumulation of ER-IM complexes. Electron tomography revealed that the ER-IM complex appears as a subdomain of the ER that formed a cradle encircling the IM, and showed that both ER and isolation membranes are interconnected.
          Article 0 comments Cited 354 times – based on 0 reviews     Review now
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            The MBOAT7-TMC4 Variant rs641738 Increases Risk of Nonalcoholic Fatty Liver Disease in Individuals of European Descent.

            Rosellina Mancina, Paola Dongiovanni, Salvatore Petta … (2016)
            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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              Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms.

              E Bugianesi, A Gastaldelli, E Vanni … (2005)
              Non-alcoholic fatty liver disease (NAFLD) has been associated with the metabolic syndrome. However, it is not clear whether insulin resistance is an independent feature of NAFLD, and it remains to be determined which of the in vivo actions of insulin are impaired in this condition. We performed a two-step (1.5 and 6 pmol min(-1) kg(-1)) euglycaemic insulin clamp coupled with tracer infusion ([6,6-2H2]glucose and [2H5]glycerol) and indirect calorimetry in 12 non-obese, normolipidaemic, normotensive, non-diabetic patients with biopsy-proven NAFLD and six control subjects. In NAFLD patients, endogenous glucose production (basal and during the clamp) was normal; however, peripheral glucose disposal was markedly decreased (by 30% and 45% at the low and high insulin doses, respectively, p<0.0001) at higher plasma insulin levels (p=0.05), due to impaired glucose oxidation (p=0.003) and glycogen synthesis (p<0.001). Compared with control subjects, glycerol appearance and lipid oxidation were significantly increased in NAFLD patients in the basal state, and were suppressed by insulin to a lesser extent (p<0.05-0.001). The lag phase of the in vitro copper-catalysed peroxidation of LDL particles was significantly shorter in the patients than in the control subjects (48+/-12 vs 63+/-13 min, p<0.04). Lipid oxidation was significantly related to endogenous glucose production, glucose disposal, the degree of hepatic steatosis, and LDL oxidisability. Insulin resistance appears to be an intrinsic defect in NAFLD, with the metabolic pattern observed indicating that adipose tissue is an important site.
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                Author and article information

                Contributors
                Paola Dongiovanni
                Journal
                Journal ID (nlm-ta): EBioMedicine
                Journal ID (iso-abbrev): EBioMedicine
                Title: EBioMedicine
                Publisher: Elsevier
                ISSN (Electronic): 2352-3964
                Publication date PMC-release: 03 July 2020
                Publication date Collection: July 2020
                Publication date (Electronic): 03 July 2020
                Volume: 57
                Electronic Location Identifier: 102866
                Affiliations
                [a ]General Medicine and Metabolic Diseases, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milano, Milan, Italy
                [b ]Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
                [c ]Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
                Author notes
                Article
                Publisher ID: S2352-3964(20)30241-3 Publisher ID: 102866
                DOI: 10.1016/j.ebiom.2020.102866
                PMC ID: 7339032
                PubMed ID: 32629394
                SO-VID: 2ed5d0f4-31d2-4416-b6a7-738cd3debdb9
                Copyright © © 2020 The Author(s)
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 11 May 2020
                Date revision received : 12 June 2020
                Date accepted : 16 June 2020
                Categories
                Subject: Review

                Keywords: mboat7,lpiat1,mafld,nash,hyperinsulinemia,insulin resistance,phospholipids
                Data availability:
                Keywords: mboat7, lpiat1, mafld, nash, hyperinsulinemia, insulin resistance, phospholipids

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