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Myeloid Lpcat3 Deficiency Promotes Hepatic Steatosis In High-Fat Diet Fed Mice

Thomas Bourgeois 1 Charles Thomas 1 A. Jalil David Masson 1 Jacques Grober 1 
1 LIPNESS - Equipe LIPNESS (LNC - U1231)
LNC - Lipides - Nutrition - Cancer [Dijon - U1231]
Abstract : Background and Aims: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and share common risk factors with atherosclerosis. Excessive hepatic lipid accumulation promotes macrophages/Kupffer cells activation, resulting in exacerbation of insulin resistance and progression of nonalcoholic steatohepatitis (NASH). The purpose of this study was to investigate the impact of a myeloid deletion of lysophosphatidylcholine acyltransferase 3 (LPCAT3) on these metabolic disorders. This enzyme, involved in phospholipid remodeling, inserts mainly arachidonic acid (AA) into cell membranes., Methods: Lpcat3flox/floxLysMCre mice (Lpcat3KOMac) were fed a high fat diet for 16 weeks. Mass and food intake were measured weekly and metabolic parameters were assessed by in vivo test (OGTT, ITT, and PTT). Liver macrophages were isolated for gene expression analysis and primary hepatocytes to assess triglyceride content, fatty acid oxidation and gene expression. Histological sections were used to quantify macrophage infiltration and liver steatosis. Results: While no differences were observed on systemic metabolic parameters and in weight gain or fat mass after a 16 week high fat diet, specific hepatic alterations were observed in Lpcat3KOMac mice, including higher liver macrophage infiltration and hepatic macrovesicular steatosis associated with liver triglycerides accumulation (40% increase in Lpcat3KOMac). Interestingly, a decrease of fatty acid oxidation is observed in primary hepatocytes of Lpcat3KOMac mice. Conclusions: Our data demonstrate that alteration of arachidonic acid metabolism in macrophages specifically affect liver triglyceride accumulation in mice indicating that these metabolic pathways are interesting therapeutic targets to investigate in the field of NAFLD.
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Submitted on : Tuesday, February 4, 2020 - 9:38:05 AM
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Thomas Bourgeois, Charles Thomas, A. Jalil, David Masson, Jacques Grober. Myeloid Lpcat3 Deficiency Promotes Hepatic Steatosis In High-Fat Diet Fed Mice. Atherosclerosis, 2019, 287, pp.e1. ⟨10.1016/j.atherosclerosis.2019.06.002⟩. ⟨hal-02465706⟩



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