Biochimica et biophysica acta. Molecular and cell biology of lipids最新文献

The disruption of the diurnal rhythm has been recognized as a significant contributing factor to metabolic dysregulation. The important role of gut microbiota and bile acid metabolism has attracted extensive attention. However, the function of the gut microbiota-bile acid axis in regulating the diurnal rhythms of metabolic homeostasis remains largely unknown. Herein, we aimed to investigate the interplay between rhythmicity of host metabolism and gut microbiota-bile acid axis, as well as to assess the impact of obesity on them. We found that high fat diet feeding and Leptin gene deficiency (ob/ob) significantly disturbed the rhythmic patterns of insulin sensitivity and serum total cholesterol levels. The bile acid profiling unveiled a conspicuous diurnal rhythm oscillation of ursodeoxycholic acid (UDCA) in lean mice, concomitant with fluctuations in insulin sensitivity, whereas it was absent in obese mice. The aforementioned diurnal rhythm oscillations were largely desynchronized by gut microbiota depletion, suggesting the indispensable role of gut microbiota in diurnal regulation of insulin sensitivity and bile acid metabolism. Consistently, 16S rRNA sequencing revealed that UDCA-associated bacteria exhibited diurnal rhythm oscillations that paralleled the fluctuation in insulin sensitivity. Collectively, the current study provides compelling evidence regarding the association between diurnal rhythm of insulin sensitivity and gut microbiota-bile acid axis. Moreover, we have elucidated the deleterious effects of obesity on gut microbiome-bile acid metabolism in both the genetic obesity model and the diet-induced obesity model.

Patatin-like phospholipase domain containing proteins (PNPLAs) play diverse roles in lipid metabolism. In this review, we focus on the enzymatic properties and predicted 3D structures of PNPLA1-5. PNPLA2-4 exert both catabolic and anabolic functions. Whereas PNPLA1 is predominantly expressed in the epidermis and involved in sphingolipid biosynthesis, PNPLA2 and 4 are ubiquitously expressed and exhibit several enzymatic activities, including hydrolysis and transacylation of various (glycero-)lipid species. This review summarizes known biological roles for PNPLA-mediated hydrolysis and transacylation reactions and highlights open questions concerning their physiological function.

Sphingolipids exert important roles within the cardiovascular system and related diseases. Perturbed sphingolipid metabolism was previously reported in cerebral and renal tissues of spontaneously hypertensive rats (SHR). Specific defects related to the synthesis of sphingolipids and to the metabolism of Sphingosine-1-Phospahte (S1P) were exclusively identified in the stroke-prone (SHRSP) with the respect to the stroke-resistant (SHRSR) strain.

In this study, we explored any existing perturbation in either protein or gene expression of enzymes involved in the sphingolipid pathways in cardiac tissue from both SHRSP and SHRSR strains, compared to the normotensive Wistar Kyoto (WKY) strain.

The two hypertensive rat models showed an overall perturbation of the expression of different enzymes involved in the sphingolipid metabolism in the heart. In particular, whereas the expression of the S1P-metabolizing-enzyme, SPHK2, was significantly reduced in both SHR strains, SGPL1 protein levels were decreased only in SHRSP. The protein levels of S1P receptors 1–3 were reduced only in the cardiac tissue of SHRSP, whereas S1PR2 levels were reduced in both SHR strains. The de novo synthesis of sphingolipids was aberrant in the two hypertensive strains. A significant reduction of mRNA expression of the Sgms1 and Smpd3 enzymes, implicated in the metabolism of sphingomyelin, was found in both hypertensive strains. Interestingly, Smpd2, devoted to sphingomyelin degradation, was reduced only in the heart of SHRSP.

In conclusion, alterations in the expression of sphingolipid-metabolizing enzymes may be involved in the susceptibility to cardiac damage of hypertensive rat strains. Specific differences detected in the SHRSP, however, deserve further elucidation.

Our previous studies have implicated an important role of adipokine chemerin in exercise-induced improvements of glycolipid metabolism and fatty liver in diabetes rat, but the underlying mechanisms remain unknown. This study first used an exogenous chemerin supplement to clarify the roles of decreased chemerin in exercised diabetes mice and possible mechanisms of glucose and lipid metabolism key enzymes and proteins [such as adipose triglyceride lipase (ATGL), lipoprotein lipase (LPL), phosphoenolpyruvate carboxykinase (PEPCK), and glucose transporter 4 (GLUT4)]. In addition, two kinds of adipose-specific chemerin knockout mice were generated to demonstrate the regulation of chemerin on glucose and lipid metabolism enzymes and proteins. We found that in diabetes mice, exercise-induced improvements of glucose and lipid metabolism and fatty liver, and exercise-induced increases of ATGL, LPL, and GLUT4 in liver, gastrocnemius and fat were reversed by exogenous chemerin. Furthermore, in chemerin knockdown mice, chemerin(−/−)∙adiponectin mice had lower body fat mass, improved blood glucose and lipid, and no fatty liver; while chemerin(−/−)∙fabp4 mice had hyperlipemia and unchanged body fat mass. Peroxisome proliferator-activated receptor γ (PPARγ), ATGL, LPL, GLUT4 and PEPCK in the liver and gastrocnemius had improve changes in chemerin(−/−)·adiponectin mice while deteriorated alterations in chemerin(−/−)·fabp4 mice, although PPARγ, ATGL, LPL, and GLUT4 increased in the fat of two kinds of chemerin(−/−) mice.

Conclusions

Decreased chemerin exerts an important role in exercise-induced improvements of glucose and lipid metabolism and fatty liver in diabetes mice, which was likely to be through PPARγ mediating elevations of ATGL, LPL and GLUT4 in peripheral metabolic organs.

Filamentous fungi undergo significant cellular morphological changes during their life cycle. It has recently been reported that deletions of genes that are involved in phospholipid synthesis led to abnormal hyphal morphology and differentiation in filamentous fungi. Although these results suggest the importance of phospholipid balance in their life cycle, comprehensive analyses of cellular phospholipids are limited. Here, we performed lipidomic analysis of A. nidulans during morphological changes in a liquid medium and of colonies on a solid medium. We observed that the phospholipid composition and transcription of the genes involved in phospholipid synthesis changed dynamically during the life cycle. Specifically, the levels of phosphatidylethanolamine, and highly unsaturated phospholipids increased during the establishment of polarity. Furthermore, we demonstrated that the phospholipid composition in the hyphae at colony margins is similar to that during conidial germination. Furthermore, we demonstrated that common and characteristic phospholipid changes occurred during germination in A. nidulans and A. oryzae, and that species-specific changes also occurred. These results suggest that the exquisite regulation of phospholipid composition is crucial for the growth and differentiation of filamentous fungi.

Hypertrophy of adipocytes represents the main cause of obesity. We investigated in vitro the changes associated with adipocyte differentiation and hypertrophy focusing on the nuclear morphometry and chromatin epigenetic remodelling. The 3 T3-L1 pre-adipocytes were firstly differentiated into mature adipocytes, then cultured with long-chain fatty acids to induce hypertrophy. Confocal and super-resolution stimulation emission depletion (STED) microscopy combined with ELISA assays allowed us to explore nuclear architecture, chromatin distribution and epigenetic modifications. In each condition, we quantified the triglyceride accumulation, the mRNA expression of adipogenesis and dysfunction markers, the release of five pro-inflammatory cytokines. Confocal microscopy revealed larger volume and less elongated shape of the nuclei in both mature and hypertrophic cells respect to pre-adipocytes, and a trend toward reduced chromatin compaction. Compared to mature adipocytes, the hypertrophic phenotype showed larger triglyceride content, increased PPARγ expression reduced IL-1a release, and up-regulation of a pool of genes markers for adipose tissue dysfunction. Moreover, a remodelling of both epigenome and chromatin organization was observed in hypertrophic adipocytes, with an increase in the average fluorescence of H3K9 acetylated domains in parallel with the increase in KAT2A expression, and a global hypomethylation of DNA. These findings making light on the nuclear changes during adipocyte differentiation and hypertrophy might help the strategies for treating obesity and metabolic complications.

Two distinct diacylglycerol acyltransferases (DGAT1 and DGAT2) catalyze the final committed step of triacylglycerol (TG) synthesis in hepatocytes. After its synthesis in the endoplasmic reticulum (ER) TG is either stored in cytosolic lipid droplets (LDs) or is assembled into very low-density lipoproteins in the ER lumen. TG stored in cytosolic LDs is hydrolyzed by adipose triglyceride lipase (ATGL) and the released fatty acids are converted to energy by oxidation in mitochondria. We hypothesized that targeting/association of ATGL to LDs would differ depending on whether the TG stores were generated through DGAT1 or DGAT2 activities. Individual inhibition of DGAT1 or DGAT2 in Huh7 hepatocytes incubated with oleic acid did not yield differences in TG accretion while combined inhibition of both DGATs completely prevented TG synthesis suggesting that either DGAT can efficiently esterify exogenously supplied fatty acid. DGAT2-made TG was stored in larger LDs, whereas TG formed by DGAT1 accumulated in smaller LDs. Inactivation of DGAT1 or DGAT2 did not alter expression (mRNA or protein) of ATGL, the ATGL activator ABHD5/CGI-58, or LD coat proteins PLIN2 or PLIN5, but inactivation of both DGATs increased PLIN2 abundance despite a dramatic reduction in the number of LDs. ATGL was found to preferentially target to LDs generated by DGAT1 and fatty acids released from TG in these LDs were also preferentially used for fatty acid oxidation. Combined inhibition of DGAT2 and ATGL resulted in larger LDs, suggesting that the smaller size of DGAT1-generated LDs is the result of increased lipolysis of TG in these LDs.

Inflammation is the hallmark of most joint disorders. However, the precise regulation of induction, perpetuation, and resolution of joint inflammation is not entirely understood. Since extracellular vesicles (EVs) are critical for intercellular communication, we aim to unveil their role in these processes. Here, we investigated the EVs' dynamics and phospholipidome profile from synovial fluid (SF) of healthy equine joints and from horses with lipopolysaccharide (LPS)-induced synovitis.

LPS injection triggered a sharp increase of SF-EVs at 5-8 h post-injection, which started to decline at 24 h post-injection. Importantly, we identified significant changes in the lipid profile of SF-EVs after synovitis induction. Compared to healthy joint-derived SF-EVs (0 h), SF-EVs collected at 5, 24, and 48 h post-LPS injection were strongly increased in hexosylceramides. At the same time, phosphatidylserine, phosphatidylcholine, and sphingomyelin were decreased in SF-EVs at 5 h and 24 h post-LPS injection. Based on the lipid changes during acute inflammation, we composed specific lipid profiles associated with healthy and inflammatory state-derived SF-EVs. The sharp increase in SF-EVs during acute synovitis and the correlation of specific lipids with either healthy or inflamed states-derived SF-EVs are findings of potential interest for unveiling the role of SF-EVs in joint inflammation, as well as for the identification of EV-biomarkers of joint inflammation.

Brown adipose tissue (BAT) is thermogenic, expressing high levels of uncoupling protein-1 to convert nutrient energy to heat energy, bypassing ATP synthesis. BAT is a promising therapeutic target for treatment of obesity and type 2 diabetes since it converts fatty acids into heat but mechanisms controlling brown adipogenesis remain unclear. Knockdown of acetyl-Coenzyme A acetyltransferase 1 (ACAT1) in C3H10T1/2 cells suppressed brown adipocyte maturation during the current study and ACAT1 overexpression promoted brown adipocyte maturation. The downstream target of AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma coactivator-1-α (PGC1α), was involved in the action of ACAT1 on brown adipocyte maturation. ACAT1 overexpression enhanced AMPK phosphorylation and promoted PGC1α expression. It is suggested that ACAT1 promotes brown adipocyte maturation by activating the AMPK-PGC1α signaling pathway.