It is known that a decrease of hepatic phospholipid (PL) contents is associated with steatosis in non-alcoholic fatty liver disease patients and in rodents. We have previously reported that calcium-independent phospholipase A2 Group VIA (iPLA2beta) deficiency alleviates steatosis in morbidly obese ob/ob KO mice, by replenishing the loss of PL thus supporting the reported role of iPLA2beta in PL remodeling. Here we tested whether iPLA2beta deficiency could protect against diet-induced steatosis and whether hepatic PL composition could be modified. Feeding of WT mice with HFD (35% fat w/w) for 6 months increased body- and liver weights as well as ALT, AST, LDH, ALP, serum lipids (cholesterol and non-esterified fatty acids), and hepatic steatosis scores. All of these parameters were attenuated in whole-body iPLA2beta KO mice fed with HFD. We analyzed PL profiling by LC/MS-MS. Like ob/ob livers where all PL subclasses are decreased, HFD feeding in WT mice did significantly decrease nearly all PL subclasses except for phosphatidylethanolamine (PE). These decreases in phosphatidylcholine (PC), phosphatidylserine (PS) and phosphatidylinositol (PI) could be mainly observed in species containing mono- or polyunsaturated fatty acids (PC 34:1, PC 34:3, PC 34:2, PC 36:3, PC 36:2, PC 36:5, PC 38:5; PS 36:1, PS 36:4; PI 34:2, PI 36:3, PI 36:4, PI 28:4, PI 38:5, PI 40:4), while PE containing saturated C 16:0 and C 18:0 fatty acids PE 34:0 was the only species that increased. This resulted in an increase of the ratio between saturated and unsaturated fatty acids in total PL, PC, and PE. The decrease of total PL, unsaturated PL, and the ratio could be reversed by iPLA2beta deficiency. Consistent with our results in ob/ob livers, iPLA2beta in HFD livers was also specific for the hydrolysis of PC and PE that contained either C 16:0 or C 18:0 fatty acids on sn-1 position. However despite of steatosis protection, three out of six HFD-fed KO mice exhibited ear dermatitis suggesting systemic inflammation likely due to iPLA2beta role in immune cells. Taken together, altered hepatic membrane homeostasis with a loss of especially unsaturated PL occurred during HFD feeding. iPLA2beta deficiency rescued this loss by replenishing unsaturated fatty-acid containing PL hence restoring the membrane balance leading to steatosis protection. This study should be confirmed by using hepatocyte-specific iPLA2beta KO mice prior to establishing a strategy to inactivate hepatocyte iPLA2beta for treatment of NAFLD.
Background Polymorphisms of iPLA2β are associated with an increase of serum C-reactive protein suggesting its role in inflammation. It is known that iPla2β regulates monocyte differentiation and monocyte migration to sites of inflammation, however, its role in NASH is still elusive. We previously reported that female iPla2β-null mice fed with methionine- and choline-deficient diet (MCDD) displayed opposing phenotypes; on one hand attenuation of liver enzymes and liver fatty acids but on the other hand exacerbation of liver fibrosis (BBA 2019, 1864, 677). Here, we examined whether macrophage-specific iPla2β deletion has any effects on NASH induced by MCDD.
Polymorphisms of fatty acid transport protein 4 (FATP4) are associated with blood lipoproteins and insulin resistance. As FATP4 is localized in intracellular organelles and highly expressed in mouse small intestine, Fatp4 role in fat absorption in mice is still controversial. As our recent studies have suggested Fatp4 role in triglyceride (TAG) metabolism, we here investigated intestinal fat absorption and blood TAG-chylomicrons (CM) in villin-Cre specific inactivation of the Fatp4 gene with exon 3 deletion (entFatp4KO mice).
Polymorphisms of group VIA calcium-independent phospholipase A2 (PLA2G6) are associated with blood C-reactive protein suggesting its role in inflammation. We showed that myeloid-specific Pla2g6-deficiency in Pla2g6
Group VIA iPLA2 (iPLA2b) or PLA2G6 catalyzes hydrolysis of phospholipids at the sn-2 position, releasing a fatty acid and a lysophospholipid which has been shown to mediate neutrophil adhesion and monocyte migration in immune cells. Moreover, PLA2G6 single nucleotide polymorphism is associated with serum C-reactive protein suggesting PLA2G6 role in inflammation. Therefore, we aim to investigate whether Pla2G6 deficiency in macrophages could modulate liver injury by altering differentiation programs of lymphocyte antigen 6 complex (Ly6C) in the bone marrow.
Background Mutations of fatty acid transport protein 4 (FATP4) cause ichthyosis prematurity syndrome (IPS) characterized by skin lesions and associated with eosinophilia and allergies. We hypothesized that FATP4 may have biological functions in immune cells, particularly macrophages, as M2 macrophages are known to mediate allergic inflammation. Therefore, lysM-Cre Fatp4 deficient (KO) mice were generated and subjected to high-fat/high-cholesterol (HFHC) diet as a model of non-alcoholic steatohepatitis (NASH) and chronic stress.
Background Polymorphisms of PLA2G6 are associated with elevation of serum C-reactive protein, and PLA2G6 mutations lead to neurodegeneration and Parkinson’s disease. Age-related abnormalities including hepatic fibrosis have been reported in global Pla2g6-null mice. We recently showed that myeloid-specific Pla2g6-deficient mice exhibited NASH susceptibility (BBA 2023). We therefore evaluated whether these mutants would exhibit inflammatory fibrogenesis during aging.
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