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

Gut. 2021 Jan;70(1):180-193. doi: 10.1136/gutjnl-2020-320646.

Yuki Tanaka ¹, Yuta Shimanaka ¹, Andrea Caddeo ², Takuya Kubo ¹, Yanli Mao ¹, Tetsuya Kubota ³, Naoto Kubota ⁴ ⁵, Toshimasa Yamauchi ⁴, Rosellina Margherita Mancina ², Guido Baselli ⁶ ⁷, Panu Luukkonen ⁸ ⁹ ¹⁰, Jussi Pihlajamäki ¹¹ ¹², Hannele Yki-Järvinen ⁸ ⁹, Luca Valenti ⁶ ⁷, Hiroyuki Arai ¹ ¹³ ¹⁴, Stefano Romeo ¹⁵ ¹⁶ ¹⁷, Nozomu Kono ¹⁸

Affiliations

1 Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
2 Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
3 Division of Diabetes and Metabolism, The Institute for Adult Diseases, Asahi Life Foundation, Tokyo, Japan.
4 Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
5 Department of Clinical Nutrition Therapy, The University of Tokyo Hospital, The University of Tokyo, Tokyo, Japan.
6 Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy.
7 Translational Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy.
8 Department of Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
9 Minerva Foundation Institute for Medical Research, Helsinki, Finland.
10 Department of Internal Medicine, Yale University, New Haven, CT, USA, Yale University, New Haven, Connecticut, USA.
11 Department of Clinical Nutrition, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.
12 Clinical Nutrition and Obesity Center, Kuopio University Hospital, Kuopio, Finland.
13 AMED-CREST, Japan Agency for Medical Research and Development, Tokyo, Japan.
14 Present address: Laboratory of Microenvironmental and Metabolic Health Science, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
15 Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden nozomu@mol.f.u-tokyo.ac.jp stefano.romeo@wlab.gu.se.
16 Clinical Nutrition Unit, Department of Medical and Surgical Science, Magna Graecia University, Catanzaro, Italy.
17 Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden.
18 Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan nozomu@mol.f.u-tokyo.ac.jp stefano.romeo@wlab.gu.se.

PMID: 32253259 DOI: 10.1136/gutjnl-2020-320646

Abstract

Objective: Non-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.

Design: We 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.

Results: The 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.

Conclusion: We 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.

Keywords

fatty liver; hepatic fibrosis; lipid metabolism; lipids.

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