a single-nucleotide polymorphism (rs738409; C>G/I148M) in the patatin-like phospholipase domain containing 3 ( PNPLA3 , adiponutrin) gene, to be strongly associated with NAFLD. A meta-analysis of 16 studies demonstrated that homozygous carriers of PNPLA3 I148M have on the average a 73% higher liver fat content than weight-matched homozygous carriers of the major allele ( 5 ). However, NAFLD associated with PNPLA3I148M is distinct from obesity-associated common NAFLD, as it is not characterized by features of the metabolic syndrome such as hyperinsulinemia or dyslipidemia ( 1, 5 ).In vitro assays using recombinant PNPLA3 have suggested that the WT PNPLA3 (PNPLA3 WT ) hydrolyzes emulsifi ed triacylglycerol (TAG) and that the I148M substitution in PNPLA3 (PNPLA3 I148M ) abolishes this activity ( 6-8 ). Moreover, the protein was shown to display a transacylase activity ( 7 ), and to prefer oleic acid (18:1n-9) as the fatty acyl moiety ( 9 ). Opposing a putative role as a lipase, PNPLA3 is induced by glucose and insulin ( 10-12 ) and is a target gene of the lipogenic transcription factors SREBP-1c and the carbohydrate responsive element binding protein, ChREBP ( 13-16 ). Kumari et al. ( 17 ) suggested that the protein acts as lipogenic lysophosphatidic acid (LPA) acyltransferase, converting LPA to phosphatidic acid (PA), and that the I148M substitution increases this activity. Because PA acts as a precursor for both phospholipids and TAGs, this provided an alternative explanation for the hepatic fat accumulation in the PNPLA3 I148M
Resolution-phase macrophage population orchestrates active dampening of the inflammation by secreting anti-inflammatory and proresolving products including interleukin (IL)-10 and lipid mediators (LMs). We investigated the effects of both human bone marrow-derived mesenchymal stromal cells (MSCs) and MSC-derived extracellular vesicles (MSC-EVs) on mature human regulatory macrophages (Mregs). The cytokines and LMs were determined from cell culture media of Mregs cultivated with MSCs and MSC-EVs. In addition, the alterations in the expression of cell surface markers and the phagocytic ability of Mregs were investigated. Our novel findings indicate that both MSC coculture and MSC-EVs downregulated the production of IL-23 and IL-22 enhancing the anti-inflammatory phenotype of Mregs and amplifying proresolving properties. The levels of prostaglandin E2 (PGE2) were substantially upregulated in MSC coculture media, which may endorse proresolving LM class switching. In addition, our results manifest, for the first time, that MSC-EVs mediate the Mreg phenotype change via PGE2. These data suggest that both human MSC and MSC-EVs may potentiate tolerance-promoting proresolving phenotype of human Mregs.
A polymorphism of TM6SF2 associates with hepatic lipid accumulation and reduction of triacylglycerol (TAG) secretion, but the function of the encoded protein has remained enigmatic. We studied the effect of stable TM6SF2 knock-down on the lipid content and composition, mitochondrial fatty acid oxidation and organelle structure of HuH7 hepatoma cells. Knock-down of TM6SF2 resulted in intracellular accumulation of TAGs, cholesterol esters, phosphatidylcholine (PC) and phosphatidylethanolamine. In all of these lipid classes, polyunsaturated lipid species were significantly reduced while saturated and monounsaturated species increased their proportions. The PCs encountered relative and absolute arachidonic acid (AA, 20:4n-6) depletion, and AA was also reduced in the total cellular fatty acid pool. Synthesis and turnover of the hepatocellular glycerolipids was enhanced. The TM6SF2 knock-down cells secreted lipoprotein-like particles with a smaller diameter than in the controls, and more lysosome/endosome structures appeared in the knock-down cells. The mitochondrial capacity for palmitate oxidation was significantly reduced. These observations provide novel clues to TM6SF2 function and raise altered mebrane lipid composition and dynamics among the mechanism(s) by which the protein deficiency disturbs hepatic TAG secretion.
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