Journal of Lipid Research最新文献

Metabolic disorders often arise in senescent endothelial cells, which impair endothelial function, lead to diminished vasodilation, increase vascular stiffness, and ultimately contribute to CVD pathogenesis. Despite notable advancements, the molecular mechanisms driving endothelial senescence and its contribution to vascular aging remain incompletely understood, thereby limiting the development of effective therapeutic strategies. Here, we investigated the protective role of terazosin (TZ) against vascular endothelial senescence using both in vivo (aged mice) and in vitro (human umbilical vein endothelial cells) models, combined with senescence-associated β-galactosidase staining, lipidomics, and molecular docking simulations. TZ treatment significantly improved endothelium-dependent vasodilation, reduced vascular stiffness, and attenuated the expression of senescence markers in aged mice. Mechanistically, lipidomics revealed that TZ reduced intracellular palmitic acid (PA) accumulation in senescent endothelial cells. Furthermore, clinical observations confirmed decreased plasma PA levels and improved endothelial function in patients receiving TZ. Monoglyceride lipase (MGLL), which hydrolyzes monoglycerides into PA and glycerol, was markedly upregulated in senescent endothelial cells and aged vascular tissues. TZ directly bound to MGLL and inhibited its enzymatic activity, thereby mitigating PA-driven endothelial senescence. Collectively, these findings identify MGLL as a novel metabolic driver of endothelial senescence and establish TZ as a potential therapeutic agent for age-related vascular diseases.

Deciphering the mechanisms by which bioactive intermediates of lipid metabolism influence cell behavior is a challenging task. We previously demonstrated that de novo synthesized ceramides are authentic transducers of apoptosis and that their CERT-mediated diversion to mitochondria is sufficient to initiate BAX-dependent apoptosis. To further unravel the mechanism by which mitochondrial ceramides commit cells to death, we here developed a novel mitochondria-targeted and photocaged short-chain ceramide with a clickable alkyne group for derivatization with a fluorescent reporter. We show that this compound readily and selectively accumulates inside mitochondria in a biologically inert state. Subsequent photorelease of the ceramide moiety triggered apoptosis as evidenced by proteolytic cleavage of central components of the caspase-dependent cell death pathway. Our findings reinforce the notion that ceramides can initiate apoptotic cell death by acting directly on mitochondria and establish mitochondria-targeted photocaged ceramides as novel tools to elucidate the underlying mechanism with the spatiotemporal precision of light.

Excessive accumulation of lipids within cardiomyocytes can sometimes initiate cardiomyopathy, while in other situations excess lipids do not cause harm. To understand how pathologic and non-pathologic lipid accumulation differ, we isolated lipid droplets (LDs) from two genetically altered mouse lines and from wild-type (WT) mice after an overnight fast. The LDs from MHC-peroxisomal proliferator-activated receptor γ1(MHC-Pparg1) transgenic mice were threefold larger than those from either fasted WT or non-cardiomyopathy MHC-diacylglycerol acyl transferase 1 (MHC-Dgat1) transgenic mice. Proteomic analysis of the LD-associated membrane proteins (LDAMPs) showed that MHC-Pparg1 LDs had less perilipin (PLIN). Proteins associated with lipolysis and LD formation (CIDEs and MTP), lipid synthesis, and Pparg signaling pathways were increased in MHC-Pparg1 LDAMPs. Unlike in MHC-Pparg1, MHC-Dgat1 LDAMPs exhibited increased mitochondrial peroxidative proteins with reduced adipose triglyceride lipase (Pnpla2), and Pparg coactivator 1 alpha (Pgc1A). Cardiomyocytes from MHC-Pparg1 hearts had transmission electron microscopy (TEM) images of ongoing lipolysis and greater amounts of lipolytic proteins. In contrast, images from MHC-Dgat1 cardiomyocytes showed more lipophagy. Consistent with the proteomic study and EM images, cardiac immunofluorescence staining showed that PLIN5 protein, thought to block LD lipolysis, was markedly reduced with MHC-Pparg1 overexpression, while hormone-sensitive lipase was increased. The autophagosome marker protein LC3B was increased in MHC-Dgat1 but not in MHC-Pparg1 hearts. Potentially toxic lipids like diacylglycerols and ceramides were increased in hearts but not LDs from MHC-Pparg1 mice. Our data indicate that cardiomyocyte LDs vary in size, composition, and metabolism. Cardiotoxicity was associated with greater LD lipolysis, which we postulate leads to intracellular release of toxic lipids.

Emerging evidence implicates that meningeal lymphatic dysfunction may contribute to the pathogenesis of brain age-related diseases, suggesting its potential as a therapeutic target for brain aging. This study investigated whether long-term Omega-3 polyunsaturated fatty acids (Omega-3 PUFAs) supplementation could delay brain aging through meningeal lymphatic modulation. We randomly assigned C57BL/6J mice into control, low-dose, and high-dose Omega-3 PUFAs groups, and administered dietary supplementation for 12 months until reaching 24 months of age. We then assessed the anti-aging effects on brain function and further examined meningeal lymphatic performance in clearance capacity and immune regulation. Our findings demonstrate that long-term Omega-3 PUFAs supplementation increases docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) levels in the brain, reduces age-related neuronal loss, and improves motor and cognitive behaviors in aged mice. Additionally, it reduces the accumulation of toxic proteins (phosphorylated tau and amyloid-β) and metabolites (NADPH, succinyl-CoA, and cAMP) in the brain and decreases immune cell infiltration (CD68+ microglia and CD3+ T cells) in the central nervous system of aged mice. Furthermore, we demonstrate that these protective effects may be mediated through preservation of the meningeal lymphatic system during aging. In conclusion, this study elucidates a novel understanding of the anti-brain-aging mechanisms of Omega-3 PUFAs.

Sphingolipids are increasingly recognized as critical regulators of inflammation and cell fate decisions, with metabolites such as ceramide and sphingosine 1-phosphate exerting contrasting effects on cell survival and proliferation. In macrophages, this balance is especially important, given their central role in host defense, pathogenesis and wound healing. Here, we present a time-resolved model of sphingolipid metabolism in RAW 264.7 macrophages stimulated with KdO₂-Lipid A. By integrating measured metabolite concentrations with dynamic flux estimation and established enzyme kinetics, we systematically map dynamic changes in the sphingolipid network during inflammation. Our results reveal a three-phase pattern of sphingolipid remodeling that correlates with distinct functional states of the cell. Moreover, metabolites can be classified into "resolving" or "non-resolving" lipids based on whether they return to basal levels or remain dysregulated through the later phases of the inflammatory response. This partitioning suggests that targeted modulation of specific metabolic nodes may influence the resolution of inflammation. Importantly, our computational approach can assist in the rational design of experimental studies by pinpointing putative drug targets with maximal impact on sphingolipid homeostasis. Such targeted interventions may prevent the pathological amplification of inflammatory signals without globally suppressing essential sphingolipid functions. These findings highlight the utility of an integrative systems-level analysis for elucidating sphingolipid dynamics in macrophages and underscore its potential to guide therapeutic strategies against conditions involving dysregulated inflammation.

We aimed to investigate the relative efficacy of feeding different bile acids in preventing PNALD in neonatal pigs. Newborn pigs given total parenteral nutrition (TPN) combined with minimal enteral feeding of chenodeoxycholic acid (CDCA) or increasing doses of obeticholic acid (OCA) for 19 days. Enteral OCA (5 and 15 mg/kg), but not CDCA (30 mg/kg) reduced blood cholestasis markers compared to TPN controls and increased bile acids in the gallbladder and intestine. Major bile acids in the liver and distal intestine were CDCA, HCA, HDCA, and OCA, and their relative proportions were increased by the type of bile acid (CDCA or OCA) given enterally. High doses of OCA increased the total NR1H4-agonistic bile acid profile in the liver and intestine above 50% total bile acids. Both CDCA and OCA treatments suppressed hepatic CYP7A1 expression, but only OCA increased hepatobiliary transporters, ABCB11, ABCC4, and ABCB1. Plasma phytosterol levels were reduced and biliary levels were increased by CDCA and OCA and hepatic sterol transporters, abcg5/8, expression were increased by OCA. Both CDCA and OCA increased plasma FGF19 and OCA increased intestinal FGF19, FABP6, and SLC51A. Both CDCA and OCA increased intestinal mucosal growth, whereas CDCA increased the plasma GLP-2, GLP-1 and GIP. Enteral OCA prevented cholestasis and phytosterolemia by increased hepatic bile acid and sterol transport via induction of hepatobiliary transporter NR1H4 target genes and not by suppression of bile acid synthesis genes. We also showed an intestinal trophic action of OCA that demonstrates a dual clinical benefit of NR1H4 agonism in the prevention of PNALD in pigs.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune-mediated neuropathy that causes significant disability in patients. Although pathogenic mechanisms remain unclear, it is known that inflammation results in segmental demyelination. This study aims to investigate the plasma lipidomic profile of patients with CIDP to identify lipid patterns associated with disease activity. Using high-throughput shotgun lipidomics, we analyzed and compared the plasma lipidome of 30 patients with CIDP (mean age ± SD: 60.7 ± 12.2 years) with that of 30 individuals diagnosed with non-demyelinating neurological disorders (OND; mean age ± SD: 52.8 ± 10.3 years). Lipids were quantified in absolute [pmol] and relative concentrations [mol%], and their levels were correlated with CIDP disease activity and clinical disability scores (R-ODS, INCAT and MRC). To control for confounders such as age and weight, strongly correlated lipids were excluded. The analysis identified 669 molecular lipid species across 15 lipid classes, revealing a significant elevation in the diacylglycerol (DAG) class in CIDP patients. Furthermore, specific lipid subspecies, including triacylglycerol (TAG), DAG, and ether-linked phosphatidylcholine (PC O-), were significantly correlated with disease activity. A set of distinct lipid subspecies, including phosphatidylcholine (PC), lyso-phosphatidylcholine (LPC), phosphatidylinositol (PI), sphingomyelin (SM), and cholesterol ester (CE), showed strong associations with clinical disability scores. These findings suggest that CIDP is characterized by distinct lipidomic profiles modulated by disease activity. This dataset could pave the way for future studies in larger cohorts evaluating the potential of plasma lipid profiles to serve as biomarkers for disease activity and severity, aiding in informing clinical management.

Apolipoprotein A-V (APOA5) is a critical regulator of circulating triglyceride (TG) levels. Its deletion leads to elevated plasma TG concentrations by altering the metabolism of VLDL particles in vivo. One way APOA5 exerts its effects is through the modulation of LPL activity, specifically by disrupting inhibitory interactions between LPL and angiopoietin-like proteins (ANGPTLs). However, the impact of APOA5 on VLDL composition and its potential to alter VLDL metabolism in other ways remains poorly understood. To address this, we investigated the influence of APOA5 on the VLDL proteome, LPL activation, and hepatic remnant uptake. Using VLDL from Apoa5 KO and WT mice, we found no evidence that APOA5 directly enhances LPL activity in purified or plasma systems. However, VLDL from Apoa5 KO mice was cleared significantly more slowly by cultured hepatocytes. VLDL proteomics experiments from two independent laboratories identified altered contents of 23 proteins involved in lipoprotein metabolism, inflammation, and immune response in Apoa5 KO VLDL, including reductions in APOE and serum amyloid A1. Remarkably, reintroduction of recombinant mouse APOA5 to the KO plasma partially restored the WT VLDL proteome, including APOE, and normalized VLDL uptake by hepatocytes without altering LPL lipolysis. These findings reveal that APOA5 influences hepatic clearance of VLDL remnants by modulating particle composition, particularly APOE content. This study expands the functional scope of APOA5 in TG metabolism and underscores its role in VLDL remodeling and remnant clearance, offering new insights with implications for understanding hypertriglyceridemia and its roles in inflammation and immune response.