Journal of Lipid Research最新文献

Obesity leads to numerous illnesses and metabolic disorders, with lysophosphatidylcholine levels declining in obese patients. However, the physiological role of lysophosphatidylcholine and the regulatory mechanisms involved in modulating obesity remain largely unknown. Here, we provide evidence that 1-linoleoylglycerophosphocholine (1-LGPC) promotes adipocyte energy expenditure by activating the Kelch-like ECH-associated protein 1-nuclear factor erythroid 2-related factor 2 (NRF2) axis. Metabolomic analyses identified 1-LGPC as a characteristic metabolite that declined in the peripheral blood of obese patients. Treatment with 1-LGPC effectively alleviated high-fat diet-induced lipid accumulation in zebrafish larvae and human adipocytes. Elevated expression levels, increased oxygen consumption rates, and enhanced transcript levels indicated that uncoupling protein 1-dependent thermogenesis and mitochondrial respiration were significantly boosted. Furthermore, NRF2 expression and nuclear translocation were induced by 1-LGPC, and NRF2 inhibition triggered uncoupling protein 1 downregulation and lipid accumulation restoration, confirming the Kelch-like ECH-associated protein 1-NRF2 axis's involvement in 1-LGPC-induced energy expenditure. These findings offer preliminary insights into physiological roles and mechanisms by which 1-LGPC modulates lipid and energy metabolism, providing potential strategies for obesity intervention using clinically identified compounds.

DHA is primarily found in fish and seafood as triacylglycerols and phospholipids (PLs). Oral administration of PL DHA forms, sn-1 lysophosphatidylcholine-DHA (sn-1 LPC-DHA) and di-DHA phosphatidylcholine (di-DHA-PC), has been suggested to increase brain DHA levels by ∼100% (relative percent) and up to ∼200% (concentration) compared with controls. In contrast, triacylglycerol-DHA and nonesterified-DHA do not produce increases in brain DHA when provided in the diet. However, a subsequent study using a higher dose of sn-1 LPC-DHA did not confirm these findings and reported no significant increase in brain DHA. To address these inconsistencies, we aimed to replicate previous investigations of PL-DHA forms (LPC and PC) and their impact on brain DHA levels. Mice were randomly divided into one of four groups and received a daily gavage for 30 days of 80 μl of either corn oil alone (control) or corn oil containing 1 mg of DHA as nonesterified DHA, sn-1 LPC-DHA, or di-DHA-PC. DHA relative percent and concentrations were determined in brain regions (cortex, cerebellum, hippocampus, amygdala, striatum, and remainder of brain) and plasma using GC-flame ionization detection. Following treatment, no significant differences in DHA relative percent or concentration were observed between control and/or treatment groups in any brain region. Relative percent of plasma DHA was significantly elevated in all DHA-treated groups compared with the control group, confirming systemic absorption of the supplemented DHA. Our results demonstrate that dietary DHA provided as sn-1 LPC-DHA or di-DHA-PC does not increase brain DHA levels compared with nonesterified-DHA or the control group, failing to reproduce prior reports.

The Orm family of proteins inhibit serine palmitoyltransferase-the enzyme that catalyzes the first step in sphingolipid synthesis. In S. cerevisiae, the two Orm proteins are thought to function redundantly in suppressing sphingolipid production. Here, we show that Orm2, in contrast, promotes production of complex sphingolipids by regulating Ypk1-dependent phosphorylation of Orm1 through control of long-chain base (LCB) levels, the initial precursors in the sphingolipid biosynthesis pathway. Using targeted lipidomic analysis of orm1Δ versus orm2Δ strains, the results showed that Orm1 regulates complex sphingolipid levels, whereas Orm2 primarily modulates the production of LCBs. We then show that reduced Orm1 phosphorylation in orm2Δ cells was mediated by LCB-dependent inactivation of AGC family protein kinase Ypk1. We further demonstrate that this Orm2-LCBs-Ypk1-Orm1 regulatory module is responsive to nitrogen availability, promoting sphingolipid synthesis under nitrogen-rich conditions. Functionally, this pathway is required for nitrogen-induced endocytosis of the general amino acid permease Gap1. Together, our findings reveal that Orm2 governs sphingolipid production and downstream endocytic events via a nitrogen-responsive LCBs-Ypk1-Orm1 signaling pathway, linking nitrogen status to sphingolipid metabolism and membrane trafficking.

Sphingomyelin synthase-related protein (SMSr) belongs to the SMS family; however, it cannot synthesize SM. We reported that SMSr is a phosphatidylethanolamine-specific phospholipase C, which is associated with metabolic dysfunction-associated fatty liver disease (MAFLD). However, the mechanism is unknown. Based on hierarchical clustering of the samples from the human Genotype-Tissue Expression project, we found that SMSr and serine palmitoyltransferase (SPT), the key enzyme for sphingolipid biosynthesis, as well as certain sphingolipid metabolism-related genes, belong to the same co-expression cluster in the liver and adipose tissues. We also found that Smsr expression is positively associated with Sptlc1 and Sptlc2 expression in both tissues of both genders. In a mouse study, we found that Smsr overexpression induced while Smsr knockout (KO) (under a high-fat diet) reduced SPT activity, thus, influencing most of the tested sphingolipids. Further, we found that PE treatment reversed Smsr overexpression-mediated SPTLC2 upregulation. PE supplement also reduced liver microsome SPT activity in a dose-dependent manner. Furthermore, we demonstrated that SMSr interacts with SPTLC2 in vivo. Thus, SMSr, as a member in the sphingolipid biosynthesis pathway, regulates SPT. Perturbation of SPT activity has been linked to the prevention of MAFLD and cardiovascular diseases. However, the approach to finding an SPT-specific inhibitor, as a drug, has not been successful so far. Importantly, global Smsr KO mice are viable and healthy; therefore, inhibiting SPT activity by reducing PE, mediated by SMSr/PE-PLC activity, could provide a novel approach for preventing and treating MAFLD.

Autism spectrum disorders are neurodevelopmental conditions that pose substantial diagnostic and therapeutic challenges. Maternal exposure to valproic acid (VPA) during pregnancy is a well-established risk factor associated with autism-like behaviors in offspring. This study characterized the metabolic phenotypes in the brain tissue of larval zebrafish following VPA exposure. Zebrafish were exposed to 4 μM VPA from 2 h postfertilization until 4.5 days postfertilization, and locomotor activity was assessed at 14 days postfertilization. Comprehensive metabolomic profiling via ultra-performance liquid chromatography-MS/MS identified 2,613 metabolites in brain tissue, of which 50 showed potential links to autism (CTRL_CV <15%, VPA_CV <20%). Significant reductions were observed in the levels of glutamine, glutamate, and triglyceride (TG). Nile red staining confirmed profoundly decreased TG deposition in the dorsal telencephalon (pallium), habenula, and cerebellum of VPA-exposed zebrafish. Furthermore, in vivo imaging revealed attenuated fluorescence intensity in excitatory glutamatergic and inhibitory gamma-aminobutyric acidergic neurons within the habenular nucleus and optic tectum, corresponding to reduced TG levels. Conversely, the cerebellar corpus (central cerebellar body) and inferior olive nucleus exhibited an increase in excitatory glutamatergic neurons and a reduction in inhibitory gamma-aminobutyric acidergic neurons, indicating an excitatory and inhibitory imbalance. Collectively, these findings suggest that VPA may promote autism pathogenesis by disrupting the glutamine-glutamate cycle and impairing TG metabolism in the zebrafish brain. These findings offer novel insights into metabolic dysfunction in autism spectrum disorders and may facilitate the identification of potential diagnostic biomarkers.

The bile acid reabsorption inhibitors (BARIs) elobixibat, maralixibat, and odevixibat are clinically used inhibitors of the intestinal bile acid transporter ASBT (SLC10A2). An additional BARI compound, linerixibat, is still under clinical development. In the present study, potential cross-reactivities against the closely related hepatic bile acid carrier and hepatitis B virus entry receptor NTCP (SLC10A1), as well as the steroid sulfate uptake carrier SOAT (SLC10A6) were analyzed. All BARIs potently inhibited ASBT (IC₅₀ = 0.1-1.0 μM). Among them, elobixibat, maralixibat, and odevixibat also inhibited SOAT (IC₅₀ = 3.2-5.9 μM) and NTCP (IC₅₀ = 10-99 μM). Furthermore, all four BARIs inhibited the hepatic drug transporters OATP1B1, OATP1B3, and OATP2B1 (IC₅₀ = 1.6-29 μM). Notably, ASBT inhibition by linerixibat was reversible upon washout, while maralixibat and odevixibat induced full and sustained ASBT inhibition even after removal of the inhibitor and inhibitor-free incubation over 240 min. Elobixibat and the pan-SLC10 inhibitor troglitazone revealed an intermediate effect. The ASBT S294T/I295V double mutation increased the inhibitory potency of linerixibat, suggesting a role of this domain for linerixibat binding. In contrast, this mutation had no significant effect on the ASBT inhibition by elobixibat, maralixibat, and odevixibat, indicating distinct binding sites. In conclusion, the analyzed BARIs revealed carrier cross-reactivities with NTCP, SOAT, and members of the OATP family, but behaved differently regarding their time-dependent inhibition and potential inhibitor binding sites.

Asprosin is a recently discovered adipokine involved in the regulation of hepatic gluconeogenesis and appetite, but its role in hepatic lipid metabolism, a key aspect of metabolic dysfunction-associated steatotic liver disease (MASLD), is unknown. This study aimed to investigate whether asprosin could regulate hepatic lipid metabolism in vitro and in an animal model and to determine the potential association between circulating levels of asprosin and the severity of hepatic steatosis in humans. The effects of asprosin on the metabolic phenotype of mice with diet-induced obesity (DIO), as well as on de novo lipogenesis, β-oxidation, and mitochondrial function, were analyzed in both cultured primary hepatocytes and mice by assessing mRNA and protein levels of metabolic pathway components, along with mitochondrial function. Furthermore, serum asprosin levels were measured in 314 subjects who also underwent transient elastography. The results showed that in vitro, asprosin reduced the expression of lipogenic genes and increased those of fatty acid oxidation and mitochondrial activity in hepatocytes. In the DIO model, asprosin-treated mice showed reduced lipid accumulation, improved metabolic parameters and increased abundance of proteins of lipid catabolism. Furthermore, asprosin levels were positively correlated with the controlled attenuation parameter (CAP) and liver stiffness (KPa) in FibroScan measurements. Higher asprosin levels were observed in subjects with severe steatosis (S2 and S3) compared to those without (S0). This adipokine appears to play a protective role in early hepatic steatosis by modulating lipid metabolism and enhancing mitochondrial function.

Polyunsaturated fatty acids (PUFAs) are indispensable for proper neuronal function. PUFA deficiency and imbalance have been linked to various brain disorders, including major depressive disorder (MDD) and anxiety. However, the effects of PUFAs on brain disorders remain inconclusive, and the extent of their shared genetic determinants is largely unknown. We utilized genome-wide association summary statistics from six phenotypes of circulating PUFAs (N = 114,999) and 20 brain disorders (N = 9,725-762,917). We performed genome-wide analysis for each of the 120 trait pairs. We evaluated the correlation of genetic effects with genetic correlation, estimated the number of shared genetic variants with polygenic overlap, and prioritized potential causal relationships with two-sample Mendelian randomization (MR). We pinpointed specific shared variants with colocalization and statistical fine-mapping. Genetic correlation and polygenic overlap analyses revealed a widespread but moderate shared genetic basis for 77 PUFA-brain disorder trait pairs. MR suggested potential causal relationships for 16 pairs. Colocalization identified 40 shared loci (13 unique) and 22 candidate shared causal variants, including rs1260326 (GCKR), rs174564 (FADS2), and rs4818766 (ADARB1). These genes were mapped to lipid metabolism pathways. Integrating evidence from multiple approaches, we prioritized four PUFA-brain disorder pairs with potential causal links, including PUFA% with MDD, and omega-6% with alcohol consumption. These findings reveal a widespread but moderate shared genetic basis between PUFAs and brain disorders, pinpoint specific shared variants, and provide support for potential effects of PUFAs on certain brain disorders, especially MDD and alcohol consumption. Future studies are needed to elucidate potential causal effects.

Mitochondria are fundamental to energy homeostasis and undergo dynamic changes in brown and beige fat. Mitochondrial dysfunctions impair thermogenic capacity and cause obesity-associated metabolic diseases. The phospholipid composition is crucial for maintaining mitochondrial function and fission-fusion processes. Here, we described early B-cell factor 2 (EBF2), a transcription factor pivotal for brown adipose tissue (BAT) development and function that regulates the integrity of mitochondrial membrane composition, function, and dynamics in brown adipocytes. Strikingly, Myf5^Cre-driven targeted deletion of Ebf2 in BAT drastically reduces cardiolipin and phosphatidylethanolamine abundance and alters acyl chain remodeling of major phospholipids. BAT mitochondria of Ebf2-KO neonates exhibit a severe reduction of DRP1 and OPA1, key regulators of mitochondrial fission-fusion dynamics; further, Ebf2 deletion impairs fragmentation-fusion events in BAT. Mechanistically, EBF2 directly binds to key genes, including Srebf1, which are involved in membrane lipid metabolism and differentially regulate their expression. Also, the deletion of Ebf2 downregulates cardiolipin and phosphatidylethanolamine-synthesizing genes and accumulates phosphatidylserine and sphingomyelin levels in mitochondria. Thus, the deletion of Ebf2 perturbs the acyl chain remodeling of mitochondrial lipids and affects the fission-fusion cycle in neonatal brown adipocytes. To conclude, Ebf2 is crucial for regulating the levels and remodeling of bilayer and nonbilayer-forming lipids to conserve mitochondrial metabolism.

In an interplay with parenchymal cells of metabolically active organs, such as heart and adipose tissues, vascular endothelial cells are important for the regulation of nutrient uptake and organ-specific energy metabolism. Based on high expression of the scavenger receptor class B type I (SR-B1) in capillary endothelial cells of white adipose tissue and brown adipose tissue (BAT), we proposed a functional role for this receptor in lipid handling and adaptive thermogenesis. To address this hypothesis, we generated mice with an endothelial-specific KO of SR-B1 and performed metabolic turnover and indirect calorimetry studies in response to environmental cues, such as cold exposure and high-fat diet feeding. Compared with control littermates, endothelial-specific SR-B1 KO mice had substantially lower SR-B1 mRNA and protein levels in heart, skeletal muscle, BAT, and white adipose tissue but not in liver, indicating that SR-B1 is primarily expressed by endothelial cells in peripheral organs. We did not detect major differences in gene expression of thermogenic and lipid-handling genes, energy expenditure assessed by indirect calorimetry, or clearance of metabolic tracers for glucose and triglycerides between endothelial SR-B1 KO mice and controls under basal conditions, thermogenic activation, or high-fat diet feeding. However, consistent with the importance of SR-B1 expression by hepatocytes for HDL metabolism, mice lacking endothelial SR-B1 had lower selective cholesterol uptake in the heart and BAT compared with control littermates. We conclude that endothelial SR-B1 is not essential for adaptive thermogenesis and handling of triglyceride-rich lipoproteins, but it is involved in regulating cholesterol homeostasis in the heart and BAT.