PMID- 36334837 OWN - NLM STAT- MEDLINE DCOM- 20221122 LR - 20230217 IS - 1879-260X (Electronic) IS - 0925-4439 (Linking) VI - 1869 IP - 1 DP - 2023 Jan 1 TI - Myeloid- and hepatocyte-specific deletion of group VIA calcium-independent phospholipase A2 leads to dichotomous opposing phenotypes during MCD diet-induced NASH. PG - 166590 LID - S0925-4439(22)00261-7 [pii] LID - 10.1016/j.bbadis.2022.166590 [doi] AB - Polymorphisms of phospholipase A2VIA (iPLA2beta or PLA2G6) are associated with body weights and blood C-reactive protein. The role of iPLA2beta/PLA2G6 in non-alcoholic steatohepatitis (NASH) is still elusive because female iPla2beta-null mice showed attenuated hepatic steatosis but exacerbated hepatic fibrosis after feeding with methionine- and choline-deficient diet (MCDD). Herein, female mice with myeloid- (MPla2g6(-/-)) and hepatocyte- (LPla2g6(-/-)) specific PLA2G6 deletion were generated and phenotyped after MCDD feeding. Without any effects on hepatic steatosis, MCDD-fed MPla2g6(-/-) mice showed further exaggeration of liver inflammation and fibrosis as well as elevation of plasma TNFalpha, CCL2, and circulating monocytes. Bone-marrow-derived macrophages (BMDMs) from MPla2g6(-/-) mice displayed upregulation of PPARgamma and CEBPalpha proteins, and elevated release of IL6 and CXCL1 under LPS stimulation. LPS-stimulated BMDMs from MCDD-fed MPla2g6(-/-) mice showed suppressed expression of M1 Tnfa and Il6, but marked upregulation of M2 Arg1, Chil3, IL10, and IL13 as well as chemokine receptors Ccr2 and Ccr5. This in vitro shift was associated with exaggeration of hepatic M1/M2 cytokines, chemokines/chemokine receptors, and fibrosis genes. Contrarily, MCDD-fed LPla2g6(-/-) mice showed a complete protection which was associated with upregulation of Ppara/PPARalpha and attenuated expression of Pparg/PPARgamma, fatty-acid uptake, triglyceride synthesis, and de novo lipogenesis genes. Interestingly, LPla2g6(-/-) mice fed with chow or MCDD displayed an attenuation of blood monocytes and elevation of anti-inflammatory lipoxin A4 in plasma and liver. Thus, PLA2G6 inactivation specifically in myeloid cells and hepatocytes led to opposing phenotypes in female mice undergoing NASH. Hepatocyte-specific PLA2G6 inhibitors may be further developed for treatment of this disease. CI - Copyright (c) 2022 The Authors. Published by Elsevier B.V. All rights reserved. FAU - Jansakun, Chutima AU - Jansakun C AD - Internal Medicine IV, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany; School of Allied Health Sciences, Walailak University, Nakhon Si Thammarat 80161, Thailand. FAU - Chunglok, Warangkana AU - Chunglok W AD - School of Allied Health Sciences, Walailak University, Nakhon Si Thammarat 80161, Thailand. FAU - Altamura, Sandro AU - Altamura S AD - Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, Im Neuenheimer Feld 350, 69120 Heidelberg, Germany. FAU - Muckenthaler, Martina AU - Muckenthaler M AD - Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, Im Neuenheimer Feld 350, 69120 Heidelberg, Germany; Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), German Centre for Cardiovascular Research, Partner Site, University of Heidelberg, Germany. FAU - Staffer, Simone AU - Staffer S AD - Internal Medicine IV, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. FAU - Tuma-Kellner, Sabine AU - Tuma-Kellner S AD - Internal Medicine IV, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. FAU - Merle, Uta AU - Merle U AD - Internal Medicine IV, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. FAU - Chamulitrat, Walee AU - Chamulitrat W AD - Internal Medicine IV, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. Electronic address: Walee.Chamulitrat@med.uni-heidelberg.de. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20221102 PL - Netherlands TA - Biochim Biophys Acta Mol Basis Dis JT - Biochimica et biophysica acta. Molecular basis of disease JID - 101731730 RN - EC 3.1.1.4 (Phospholipases A2, Calcium-Independent) RN - 0 (PPAR gamma) RN - 0 (Interleukin-6) RN - 0 (Lipopolysaccharides) RN - AE28F7PNPL (Methionine) RN - N91BDP6H0X (Choline) RN - 73JWT2K6T3 (Racemethionine) RN - 0 (PPAR alpha) RN - 0 (Receptors, Chemokine) RN - EC 3.1.1.4 (Pla2g6 protein, mouse) RN - EC 3.1.1.4 (Group VI Phospholipases A2) SB - IM MH - Female MH - Mice MH - Animals MH - *Non-alcoholic Fatty Liver Disease/genetics MH - Phospholipases A2, Calcium-Independent MH - PPAR gamma/genetics MH - Interleukin-6 MH - Lipopolysaccharides MH - Diet MH - Hepatocytes MH - Phenotype MH - Methionine MH - Choline MH - Racemethionine MH - PPAR alpha MH - Receptors, Chemokine MH - Group VI Phospholipases A2/genetics OTO - NOTNLM OT - Chemokines OT - Fatty liver disease OT - Group VIA phospholipase A2 OT - Liver fibrosis OT - Tissue-specific gene deletion OT - de novo lipogenesis COIS- Declaration of competing interest All authors declare no competing interest. EDAT- 2022/11/06 06:00 MHDA- 2022/11/23 06:00 CRDT- 2022/11/05 20:34 PHST- 2022/07/13 00:00 [received] PHST- 2022/10/25 00:00 [revised] PHST- 2022/10/25 00:00 [accepted] PHST- 2022/11/06 06:00 [pubmed] PHST- 2022/11/23 06:00 [medline] PHST- 2022/11/05 20:34 [entrez] AID - S0925-4439(22)00261-7 [pii] AID - 10.1016/j.bbadis.2022.166590 [doi] PST - ppublish SO - Biochim Biophys Acta Mol Basis Dis. 2023 Jan 1;1869(1):166590. doi: 10.1016/j.bbadis.2022.166590. Epub 2022 Nov 2.