Journal of Lipid Research最新文献

A high-fat diet (HFD) induces metabolic dysfunction early, before the onset of the classic obese phenotype. However, understanding this early process remains limited, and potential diagnostic systems are still poorly investigated, particularly in childhood obesity. Continuous blood glucose monitoring was performed in mice to evaluate the early metabolic effects of HFD exposure. Metabolomic and transcriptomic analyses were conducted to characterize metabolic and transcriptional changes at various HFD feeding stages and investigate underlying mechanisms. Venn analysis was applied to identify metabolites specific to early HFD exposure. These metabolites were further compared with those detected in obese children to identify potential early warning biomarkers of obesity. Week 3 of HFD feeding was identified as a critical turning point in metabolic dysfunction in mice. Metabolomic profiling revealed that significant metabolic remodeling had occurred before glucose intolerance, particularly involving alterations in tryptophan metabolism, polyamine metabolism, and glycerophospholipid metabolism. Moreover, 54 HFD-specific metabolites were identified during this early stage. Further analysis identified serotonin, formiminoglutamate, inosine, and spermine as potential early warning biomarkers for HFD-induced obesity. Finally, transcriptomic profiling revealed early activation of interleukin-17A and type I interferon pathways, implicating immune involvement in metabolic perturbations. Early HFD exposure induces metabolic reprogramming before the onset of glucose intolerance. These_under_edi findings provide new insights into the mechanisms of diet-induced metabolic dysfunction and support the identification of potential biomarkers for early detection, particularly in childhood obesity. Early high-fat diet exposure induces metabolic reprogramming before glucose intolerance, characterized by alterations in tryptophan and polyamine metabolism and revealing candidate early biomarkers of obesity.

Lipoprotein secretion is a complex, highly regulated multi-step process that ensures the efficient transport of lipids from cells into the bloodstream, supporting overall metabolic health. The secretion of very-low-density lipoprotein (VLDL) relies on the proper assembly and movement of phospholipids within cellular membranes, particularly the endoplasmic reticulum (ER). Changes in the composition and dynamics of phospholipids can affect lipoprotein size, lipid loading, and, ultimately, the ability of VLDL to be secreted. Scramblases are a class of transmembrane proteins that facilitate the movement of phospholipids between the inner and outer leaflets of membrane bilayers in a bidirectional, energy-independent manner, serving an equilibrating function. They help balance phospholipids to reduce mechanical strain and curvature in membranes, which is critical for various cellular processes, including autophagy. Recent evidence suggests that the scramblases TMEM41B and VMP1 play essential roles in regulating VLDL secretion. Loss of hepatic TMEM41B or VMP1 results in severe defects in VLDL secretion and leads to the rapid development of metabolic dysfunction-associated steatohepatitis (MASH) in mice. In this review, we discuss the latest advancements in understanding these lipid scramblases, highlighting their similarities and distinct roles in maintaining lipid homeostasis, membrane dynamics, autophagy, and VLDL secretion in the pathogenesis of MASH.

Constitutive photomorphogenesis mutant 9 (COP9) signalosome (CSN) is composed of eight subunits (CSN1 through CSN8). It acts as an essential regulator of Cullin-RING-ubiquitin ligases (CRLs), which target critical cellular regulators for degradation via the ubiquitin (Ub) proteasome pathway. The role of CSN in adipose tissue development and function has not yet been studied. We sought to determine the role of CSN8, the smallest subunit of the CSN complex, in adipogenesis, adipose tissue maintenance, and metabolic balance. We first found that CSN8 level remained constant during adipogenesis and knocking down CSN8 by CRISPR/Cas9 did not impair adipocyte differentiation. Notably, mice with adipocyte-specific Csn8 gene deletion (Csn8^AKO) showed disrupted CSN holo-complex formation and Cullin deneddylation, leading to the loss of white and brown adipose tissue. Csn8^AKO mice displayed insulin resistance while maintaining glucose tolerance. They showed increased food intake and a trend toward higher energy expenditure but were cold-intolerant. Bulk RNA sequencing revealed that CSN deficiency caused significant remodeling of white and brown adipose tissues, characterized by adipocyte death and inflammation. Specifically, white and brown adipose tissues lacking CSN8 exhibited marked upregulation of apoptotic and pyroptotic cell death, which was associated with alterations in ubiquitination and proteasome activity. In addition, Csn8^AKO mice were protected from high-fat diet-induced adipose tissue expansion but developed notable hepatomegaly, steatosis, and insulin resistance. Taken together, our data highlights that CSN8/CSN is crucial for maintaining protein homeostasis in adipose tissue, promoting adipocyte survival, supporting adipose tissue maintenance, and overall metabolic health.

Microglia lipid metabolism plays a crucial role in maintaining immune function and supporting neuronal health. Previous studies have shown that a high-fat diet (HFD) promotes lipid accumulation in microglia, while disruption of lipid uptake and utilization impair neuroimmune competency and accelerate obesity in response to a HFD, highlighting the importance of lipid processing under obesogenic conditions. However, whether enhancing microglial lipid metabolism can restore their immune function and mitigate obesity-associated hypothalamic dysfunction remains unclear. In this study, we investigated whether activation of peroxisome proliferator-activated receptor delta (PPARδ), a key regulator of lipid metabolism, could counteract obesity-related metabolic disturbances. Using thermal proteome profiling, we identified GW0742 as the most potent PPARδ agonist among those tested. Treatment of microglial cells in vitro with GW0742 enhanced phagocytosis, reduced inflammation, and improved microglial metabolic flexibility. To assess therapeutic potential in vivo, we selectively delivering GW0742 to mediobasal hypothalamic microglia in HFD-fed rats using polymeric nanoparticles (NPs-GW0742). This targeted intervention reprogrammed microglial activity and improved insulin sensitivity without affecting body weight or food intake, suggesting a direct central metabolic benefit. Our findings highlight the therapeutic potential of targeting microglial lipid metabolism to improve metabolic health in obesity.

Oxidized phospholipids (OxPL) are bioactive lipid species that circulate bound to apolipoprotein B-100 [apoB] and apolipoprotein(a) [apo(a)] and have been widely studied as biomarkers of oxidative lipid burden. When bound to apolipoprotein B-100 [OxPL-apoB] and apolipoprotein(a) [OxPL-apo(a)], they serve as informative biomarkers for CVD risk prediction, risk reclassification, and therapeutic monitoring, particularly in studies involving RNA-targeted therapies against lipoprotein(a). To date, measurement of OxPL-apoB and OxPL-apo(a) has been limited to research-use assays performed in an academic laboratory without formal clinical laboratory validation. Here we report the first full CLIA-compliant analytical validation of chemiluminescent ELISA methods for OxPL-apoB and OxPL-apo(a), enabling their implementation in a regulated clinical reference laboratory setting. The OxPL-apoB ELISA employs murine monoclonal IgG antibody MB47 to capture apoB-100-containing lipoproteins, while the OxPL-apo(a) employs murine monoclonal IgG antibody LPA4 to capture apo(a)-containing particles. In both assays, OxPL is detected by murine monoclonal IgM antibody biotin-E06. The concentration of OxPL is determined against a standard curve of phosphocholine (PC) equivalents using PC-modified bovine serum albumin. The analytical measuring range of both assays is 1.48-148.48 nmol/L PC-OxPL. Serum and plasma matrices showed minimal bias and were analytically equivalent. In healthy donors, OxPL-apoB levels ranged from <1.48 to 25.23 nmol/L PC-OxPL (mean 4.18, median 1.79 nmol/L), while OxPL-apo(a) levels ranged from <1.48 to 126.94 nmol/L PC-OxPL (mean 31.04, median 6.90 nmol/L), with strong correlation to Lp(a) concentrations (R² = 0.82). These assays provide robust tools for quantifying proatherogenic and pro-inflammatory OxPL-lipoprotein complexes in clinical, translational, and pharmacological research settings.

Chronic kidney disease (CKD) is associated with altered lipid metabolism and chronic inflammation, which both contribute to an accelerated risk of atherosclerotic cardiovascular disease. Macrophage polarization towards a pro-inflammatory phenotype plays a key role in atherosclerotic cardiovascular disease development and is mediated by a rewiring of macrophage immunometabolism. While prior studies have investigated associations between the systemic lipidome and CKD-accelerated CVD, the impact of CKD on macrophage lipid metabolism remains unknown. In this study, we profiled the macrophage lipidome in mice with and without CKD induced by 5/6 nephrectomy. After 16 weeks of a high-fat diet, thioglycollate-elicited peritoneal macrophages (PMΦ) were collected and subjected to lipidomics by LC-MS/MS. Quantification of 481 distinct lipids across 19 lipid classes identified an increased abundance of saturated C16-C24 FFAs, phosphatidylglycerols, phosphatidylethanolamines, modified ceramides, and polyunsaturated ether lipids in PMΦ from CKD mice compared to controls. PMΦ from CKD mice also exhibited decreased abundance of unsaturated FFAs, triglycerides and phosphatidylcholines. Long-chain-to-intermediate-chain acylcarnitine ratio, a metric of β-oxidation efficiency, was reduced in CKD PMΦ, without altering macrophage de novo lipogenesis suggesting a shunting of exogenous lipids towards complex lipid synthesis. Pathway enrichment analysis identified long-chain acyl-CoA synthetase 1 (ACSL1) as a potential upstream mediator of these observed changes in macrophage lipid metabolism. Expression of Acsl1 and inflammatory cytokines was increased in CKD PMΦ or following treatment with palmitate or uremic serum in RAW 264.7 macrophages. These effects were blunted by the knockdown of ACSL1 in RAW264.7 cells. Partitioning of fatty acids towards complex lipid synthesis by ACSL1 may be a mechanism underlying chronic inflammation in advancing CKD.

Polyethylene glycol (PEG) is widely used in liposome formulation due to its blocking properties and ability to prolong circulation in vivo to create biomimetic liposomes and drug delivery devices. Similarly, membrane-embedded DNA nanotechnology is increasingly used to modulate cellular behaviour and communication. However, there is a gap in knowledge in how PEG-lipid formulations can be optimized for both liposome properties and control of selective DNA hybridization. To address this, we systematically investigated the effect of liposome PEG content on DNA mediated tethering of liposomes to glass surfaces. We formulated liposomes of two different lipid compositions (DOPE/DOPC or DPhPC), with varying amounts of PEGylated lipid (0%-50%). We measured the effect of increased PEG content on liposome size and polydispersity through dynamic light scattering (DLS). Small amounts of PEG (0%-20%) introduced repulsive forces that reduced size, while large amounts of PEG (30%-50%) increased polydispersity. PEG-liposomes were then decorated with cholesterol-DNA strands and labeled with either intercalating lipid dyes or fluorescently labeled lipids. Binding to surfaces via complementary DNA strands was quantified using total internal reflection fluorescence (TIRF) microscopy. We found that PEGylation of DNA-liposomes could either block or enhance surface binding, depending on the amount of PEG. DNA-liposomes with reduced surface binding included DPhPC/DiD with 10% or 20% PEG-lipid. In contrast, DNA-liposome surface binding increased for DOPE/DOPC/DiD with increasing PEG%. This study highlights that while PEG can act to stabilize liposome formulations, its ability to block specific DNA-binding interactions on membranes is variable and dependent on membrane composition.

Lipids play a crucial role in signaling, membrane dynamics, and inflammatory regulation, yet their involvement in postoperative delirium pathogenesis remains unclear. This study examined serum lipidomic alterations in postoperative delirium and assessed the effects of dexmedetomidine treatment on these changes. Lipidomic profiling was conducted at baseline and postoperative day 1 in two independent cohorts of cardiac surgery patients. Mass spectrometry-based shotgun lipidomics and targeted lipid analyses were used to assess lipidomes and oxylipins, respectively. Cardiac surgery was associated with decreased serum lysophospholipids. Postoperative delirium was associated with increased long-chain polyunsaturated fatty acid phospholipids, particularly phosphatidylethanolamines, and elevated oxylipins. Dexmedetomidine, a potential delirium-mitigating medication, reduced long-chain polyunsaturated fatty acid phospholipids. These findings highlight lipid modulation as a potential target for postoperative delirium prevention.

Insulin resistance accompanied by hepatic steatosis is a common complication of obesity. In an effort to identify plasma lipids that could be biomarkers or causes of insulin resistance with steatosis in people with obesity, we evaluated the plasma lipidome in three distinct groups separated by adiposity, hepatic steatosis, and insulin sensitivity, assessed by using the hyperinsulinemic-euglycemic clamp procedure: i) insulin-sensitive lean (ISL, n = 13); ii) insulin-sensitive obese (ISO, n = 14); and iii) insulin-resistant obese with hepatic steatosis (IROS, n = 13). We evaluated 759 complex lipid species in 16 subclasses (including phospholipids, glycerolipids, sphingolipids, acylcarnitines, and cholesteryl esters) and 84 eicosanoids in fasting plasma samples. Total abundances of each lipid subclass (sum of species) in the ISO group were not different from values in the ISL group, whereas phosphatidylethanolamines, triglycerides, and diacylglycerols were more abundant in the IROS than in the ISO group. The abundances of only 5 individual complex lipid species were different between the ISL and ISO groups, whereas the abundances of 23 lipids were different between the ISO and IROS groups. More complex lipids were associated with insulin sensitivity (n = 124) than obesity per se (n = 7). In contrast, plasma eicosanoids were not different between the ISO and IROS groups but were greater in both groups with obesity than in the ISL group. We conclude that insulin resistance with hepatic steatosis is associated with alterations in the plasma complex lipidome, independent of adiposity, in people with obesity, whereas adiposity has a greater impact than insulin resistance on plasma eicosanoid concentrations.