Dysregulation Of Lipid Metabolism Research Articles

FABP5+ macrophages contribute to lipid metabolism dysregulation in type A aortic dissection

Type A aortic dissection (TAAD) is an acute onset disease with a high mortality rate. TAAD is caused by a tear in the aortic intima and subsequent blood infiltration. The most prominent characteristics of TAAD are aortic media degeneration and inflammatory cell infiltration, which disturb the structural integrity and function of nonimmune and immune cells in the aortic wall. However, to date, there is no systematic evaluation of the interactions between nonimmune cells and immune cells and their effects on metabolism in the context of aortic dissection. Here, multiomics, including bulk RNA-seq, single-cell RNA-seq, and lipid metabolomics, was applied to elucidate the comprehensive TAAD lipid metabolism landscape. Normally, monocytes in the stress response state secrete a variety of cytokines. Injured fibroblasts lack the ability to degrade lipids, which is suspected to contribute to a high lipid environment. Macrophages differentiate into fatty acid binding protein 5-positive (FABP5+) macrophages under the stimulation of metabolic substrates. Moreover, the upregulation of Fabp5+ macrophages were retrospectively validated in TAAD model mice and TAAD patients. Finally, Fabp5+ macrophages can generate a wide range of proinflammatory cytokines, which possibly contribute to TAAD pathogenesis.

Targeting uridine diphosphate glucuronosyltransferase 1A1 in liver disease: Current research and future directions

The current letter to the editor pertains to the manuscript entitled 'Uridine diphosphate glucuronosyltransferase 1A1 prevents the progression of liver injury'. Increased levels of uridine diphosphate glucuronosyltransferase 1A1 during liver injury could mitigate damage by reducing endoplasmic reticulum stress, oxidative stress, and dysregulated lipid metabolism, impeding hepatocyte apoptosis and necroptosis.

Modeling compound lipid homeostasis using stable isotope tracing.

Lipids represent the most diverse pool of metabolites found in cells, facilitating compartmentation, signaling, and other functions. Dysregulation of lipid metabolism is linked to disease states such as cancer and neurodegeneration. However, limited tools are available for quantifying metabolic fluxes across the lipidome. To directly measure reaction fluxes encompassing compound lipid homeostasis, we applied stable isotope tracing, high-resolution mass spectrometry, and network-based isotopologue modeling to non-small cell lung cancer (NSCLC) models. Compound lipid metabolic flux analysis (CL-MFA) enables the concurrent quantitation of fatty acid synthesis, elongation, headgroup assembly, and salvage reactions within virtually any biological system. Here, we resolve liver kinase B1 (LKB1)-mediated regulation of sphingolipid recycling in NSCLC cells and precision-cut lung slice cultures. We also demonstrate that widely used tissue culture conditions drive cells to upregulate fatty acid synthase flux to supraphysiological levels. Finally, we identify previously uncharacterized isozyme specificity of ceramide synthase inhibitors, highlighting the molecular detail revealed by CL-MFA.

Elevated Porcupine Disrupts Lipid Metabolism and Promotes Inflammatory Response in MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) presents a high incidence globally and is a major cause of cirrhosis and hepatocellular carcinoma, lacking of efficient interventions. Patients with MASLD exhibit exceeded serum levels of palmitic acid (PA). However, the association between PA and MASLD remains obscure. Gene expression omnibus dataset analysis, western blotting, mRNA-sequencing, RT-qPCR, a click chemistry-immunoprecipitation-immunofluorescence system, ELISA, lipid extraction and UHPLC-MS/MS analysis, CyTOF mass cytometry, gene knockdown via lentivirus-mediated shRNA, and high-fat methionine and choline-deficient diet-fed WT and db/db mice models were used to reveal the expression and functions of Porcupine in MASLD development both invitro and invivo. Our findings show that PA, as a crucial substrate for protein palmitoylation, induced the expression of palmitoyltransferase Porcupine in a time-dependent manner. This induction was closely associated with dysregulated lipid metabolism and stimulated inflammatory response observed invitro. Porcupine protein levels were significantly increased in liver tissues from both MASLD mice models, which was predominantly localised in lipid droplet-rich hepatocytes. Pharmacological inhibition of Porcupine by Wnt974 markedly ameliorated the aberrant lipid accumulation and inflammatory response in mouse livers. Furthermore, increased Porcupine positively correlated with CD36 at protein levels, and its inhibition or knockdown decreased CD36 protein levels via mechanisms irrelevant to transcriptional regulation, but primarily dependent on protein palmitoylation. The current study reveals that PA-induced Porcupine disrupts lipid metabolism and promotes inflammatory response during MASLD development, which can be ameliorated by the Porcupine inhibitor Wnt974. Therefore, Porcupine may be a potential pharmacological target for the treatment of MASLD.

Serum lipidome reveals lipid metabolic dysregulation in severe fever with thrombocytopenia syndrome

BackgroundSevere fever with thrombocytopenia syndrome (SFTS) is a rapidly progressing infectious disease with a high fatality rate caused by a novel bunyavirus (SFTSV). The role of lipids in viral infections is well-documented; however, the specific alterations in lipid metabolism during SFTSV infection remain elusive. This study aims to elucidate the lipid metabolic dysregulations in the early stages of SFTS patients.MethodsThis study prospectively collected peripheral blood sera from 11 critical SFTS patients, 37 mild SFTS patients, and 23 healthy controls during the early stages of infection for lipidomics analysis. A systematic bioinformatics analysis was conducted from three aspects integrating lipid differential expressions, lipid differential correlations, and lipid-clinical indices correlations to reveal the serum lipid metabolic dysregulation in SFTSV-infected individuals.ResultsOur findings reveal significant lipid metabolic dysregulation in SFTS patients. Specifically, compared to healthy controls, SFTS patients exhibited three distinct modes of lipid differential expression: increased levels of lipids including phosphatidylserine (PS), hexosylceramide (HexCer), and triglycerides (TG); decreased levels of lipids including lysophosphatidylcholine (LPC), acylcarnitine (AcCa), and cholesterol esters (ChE); and lipids showing “dual changes” including phosphatidylcholine (PC) and phosphatidylethanolamine (PE). Finally, based on lipid metabolic pathways and literature analysis, we systematically elucidated the potential mechanisms underlying lipid metabolic dysregulation in the early stage of SFTSV infection.ConclusionsOur study presents the first global serum lipidome profile and reveals the lipid metabolic dysregulation patterns in the early stage of SFTSV infection. These findings provide a new basis for the diagnosis, treatment, and further investigation of the disease.

Jolkinolide B Ameliorates Liver Inflammation and Lipogenesis by Regulating JAK/STAT3 Pathway.

Hepatic dysregulation of lipid metabolism exacerbates inflammation and enhances the progression of metabolic dysfunction-associated steatotic liver disease (MASLD). STAT3 has been linked to lipid metabolism and inflammation. Jolkinolide B (JB), derived from Euphorbia fischeriana, is known for its pharmacological anti-inflammatory and anti-tumor properties. Therefore, this study investigated whether JB affects MASLD prevention by regulating STAT3 signaling. JB attenuated steatosis and inflammatory responses in palmitic acid (PA)-treated hepatocytes. Additionally, JB treatment reduced the mRNA expression of de-novo lipogenic genes, such as acetyl-CoA carboxylase and stearoyl-CoA desaturase 1. Interestingly, JB-mediated reduction in inflammation and lipogenesis was dependent on STAT3 signaling. JB consistently modulated mitochondrial dysfunction and the mRNA expression of inflammatory cytokines by inhibiting PA-induced JAK/STAT3 activation. This study suggests that JB is a potential therapeutic agent to prevent major stages of MASLD through inhibition of JAK/STAT3 signaling in hepatocytes.

7885 Thyroid Hormone Stimulates Heaptic Lipid Metabolism in the Resolution of Liver Fibrosis

Abstract Disclosure: A. Mendoza: None. C. Wang: None. A. Lugo: None. V. Rodrigues: None. S. Houghton: None. D. Redmond: None. A. Hollenberg: None. Metabolic dysfunction-associated steatotic liver disease (MASLD) progression to steatohepatitis and fibrosis is a global health burden, leading to liver failure and death. While the pathogenesis is complex, dysregulated lipid metabolism plays a crucial role. Thyroid hormones (THs) are key metabolic regulators in the liver, promoting lipogenesis and fatty acid oxidation. Previously, we demonstrated that the carbohydrate-responsive element binding protein (ChREBP) is a critical mediator of both these processes in hepatocytes, acting downstream of the thyroid hormone receptor beta1 (TRβ1). Interestingly, while ChREBP ablation abolished TH-induced lipogenesis through downregulation of lipogenic gene expression, its role in TH-mediated fatty acid oxidation remained unclear, suggesting a multifaceted role for ChREBP in TH-regulated hepatic metabolism. Given the critical role of lipid metabolism in the progression of MASLD to metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis, we aim to delineate the mechanisms by which TH promotes the regression of fibrosis. Here, we used a carbon tetrachloride (CCL4) model of liver fibrosis in TRβ1KO and ChREBPKO mice (0.4 ul/g biweekly, 9 injections). All mice in the experiments were also on a PTU-Low Iodine diet to induce hypothyroidism. In the last week of the protocol, all mice were sorted into two groups which received either water or T3 (1ug/ml). 24 hours after the last CCL4 injection all mice were sacrificed and the livers were harvested and prepared for analysis. Herein we show that T3 promotes the resolution of liver fibrosis in wild-type mice. Importantly, this resolution was abolished in both TRβ1 and ChREBP KO mice demonstrating this pathways essential role in TH-induced resolution of fibrosis. RNA-Seq analysis of TRβ1KO mice demonstrated a dual mechanism of TH action: 1. TH upregulates gene expression in multiple metabolic pathways, suggesting a rescue of hepatic metabolism towards normal liver function and 2., TH has antifibrotic action via downregulation of pathways controlling extracellular matrix synthesis and inflammation, key drivers of fibrosis. Strikingly, ChREBP was dispensable for the antifibrotic action of TH suggesting that the ChREBP-dependent regulation of hepatic metabolism is critical for the resolution of fibrosis mediated by TH. To identify novel metabolic pathways regulated by TH via ChREBP, we intersected liver mRNA-seq from TRβ1KO mice with liver-specific ChREBP Chip-Seq and identifed multiple targets regulating autophagy that require ChREBP for their activation after TH treatment. These data suggest that the ability of ChREBP to regulate TH-induced fatty-acid oxidation is mediated by the upregulation of autophagy. This supports the notion that the ability of T3 to promote the resolution of liver fibrosis is primarily dependent of it’s ability to stimulate hepatic fatty acid metabolism. Presentation: 6/1/2024

Blockade of TREM2 ameliorates pulmonary inflammation and fibrosis by modulating sphingolipid metabolism

Pulmonary fibrosis is a chronic interstitial lung disease involving systemic inflammation and abnormal collagen deposition. Dysregulations in lipid metabolism, such as macrophage-dependent lipid catabolism, have been recognized as critical factors for the development of pulmonary fibrosis. However, little is known about the signaling pathways involved and the key regulators. Here we found that triggering receptor expressed on myeloid cells 2 (TREM2) plays a pivotal role in regulating the lipid handling capacities of pulmonary macrophages and triggering fibrosis. By integrating analysis of single-cell and bulk RNA sequencing data from patients and mice with pulmonary fibrosis, we revealed that pulmonary macrophages consist of heterogeneous populations with distinct pro-fibrotic properties, and found that both sphingolipid metabolism and the expression of chemotaxis-related genes are elevated in fibrotic lungs. TREM2, a sensor recognizing multiple lipid species, is specifically upregulated in a subset of monocyte-derived macrophages. Blockade of TREM2 by conventional/conditional knock-out or soluble TREM2 administration can attenuate bleomycin-induced pulmonary fibrosis. By utilizing scRNA Seq and lipidomics, we found that Trem2 deficiency downregulates the synthesis of various sphingomyelins, and inhibits the expression of chemokines such as Ccl2. Together, our findings not only reveal the alterations in lipidomic profiles and the atlas of pulmonary macrophages during pulmonary fibrosis, but also suggest that targeting TREM2, the crucial regulator affecting both pulmonary sphingolipid metabolism and the chemokines secretion, can benefit pulmonary fibrosis patients in the future.

NPRC promotes hepatic steatosis via USP30-mediated deubiquitination of C/EBPβ

Background and aimsMetabolic dysfunction-associated fatty liver disease (MAFLD) is a prevalent chronic liver condition characterised by dysregulated lipid metabolism. The role of Natriuretic Peptide Receptor C (NPRC), a receptor responsible for clearing natriuretic peptides, in MAFLD remains elusive. Therefore, the aim of the present study was to elucidate the role of NPRC in MAFLD progression. Approach and resultsThis study demonstrated that NPRC enhanced lipid metabolism reprogramming and accelerated MAFLD progression. Mechanistic investigations, including proteomic and ubiquitination analyses, revealed that elevated NPRC levels stabilized the C/EBPβ protein, leading to excessive lipid accumulation. The DNA-binding domain (DBD) of C/EBPβ interacted with the deubiquitinase USP30, a key regulator that inhibited K149-specific K48-linked polyubiquitination of C/EBPβ. Importantly, the ANPR region of NPRC bound to USP30, facilitating the deubiquitination of C/EBPβ. Furthermore, virtual screening identified punicalin, a natural compound, as a potential inhibitor of NPRC expression, which may reduce hepatic lipid accumulation, inflammation and fibrosis. ConclusionsOur findings indicate that NPRC recruits USP30 to mediate the deubiquitination of C/EBPβ, driving lipid metabolism reprogramming. Targeting NPRC could represent a promising therapeutic approach for MAFLD.

Glycated Hemoglobin as a Predictor of Dyslipidemia and Cardiovascular Risk in Type 2 Diabetes Mellitus

Background: Type 2 Diabetes Mellitus (T2DM) is a globally prevalent metabolic disorder that significantly increases the risk of cardiovascular disease (CVD) through mechanisms such as dyslipidemia, characterized by elevated triglycerides, low high-density lipoprotein (HDL) levels, and small dense low-density lipoprotein (LDL) particles. Glycated hemoglobin (HbA1c) is a key biomarker of glucose control and has been associated with CVD risk. Methods: This cross-sectional study aimed to evaluate the relationship between glycated hemoglobin (HbA1c) levels and lipid profiles, specifically lipid ratios, in a Jordanian population with type 2 diabetes mellitus (T2DM). A total of 140 patients with T2DM and 20 healthy controls participated. Blood samples were analyzed for fasting blood sugar (FBS), HbA1c, total cholesterol, triglycerides, high-density lipoprotein (HDL-C), and low-density lipoprotein (LDL-C) levels. HbA1c levels were grouped: A (≤7%), B (7–9%), C (9–11%), and D (>11%). Results: The T2DM group showed significantly elevated HbA1c levels compared to controls. Patients with higher HbA1c levels (Groups C and D) exhibited abnormal lipid profiles, including increased total cholesterol and triglycerides and reduced HDL-C. The LDL-C/HDL-C ratio was notably higher in patients with HbA1c >9%, indicating a potential elevated cardiovascular risk. This correlation between HbA1c and lipid profile abnormalities supports the association between poor glycemic control and lipid metabolism dysregulation. Conclusion: HbA1c levels are significantly associated with dyslipidemia, and lipid ratios serve as sensitive indicators for cardiovascular risk in T2DM patients. These findings underscore the clinical importance of monitoring HbA1c and lipid ratios to improve risk assessment and guide intervention strategies in high-risk populations.

Uncovering lipid dynamics in Staphylococcus aureus osteomyelitis using multimodal imaging mass spectrometry

Osteomyelitis occurs when Staphylococcus aureus invades the bone microenvironment, resulting in a bone marrow abscess with a spatially defined architecture of cells and biomolecules. Imaging mass spectrometry and microscopy are tools that can be employed to interrogate the lipidome of S.aureus-infected murine femurs and reveal metabolic and signaling consequences of infection. Here, nearly 250 lipids were spatially mapped to healthy and infection-associated morphological features throughout the femur, establishing composition profiles for tissue types. Ether lipids and arachidonoyl lipids were altered between cells and tissue structures in abscesses, suggesting their roles in abscess formation and inflammatory signaling. Sterols, triglycerides, bis(monoacylglycero)phosphates, and gangliosides possessed ring-like distributions throughout the abscess, suggesting a hypothesized dysregulation of lipid metabolism in a population of cells that cannot be discerned with traditional microscopy. These data provide insight into the signaling function and metabolism of cells in the fibrotic border of abscesses, likely characteristic of lipid-laden macrophages.

Cancer-associated foam cells hamper protective T cell immunity and favor tumor progression in human colon carcinogenesis

BackgroundColorectal cancer (CRC) remains a significant healthcare burden worldwide, characterized by a complex interplay between obesity and chronic inflammation. While the relationship between CRC, obesity and altered lipid metabolism is...

Dysregulation of lipid metabolism in the liver of Tspo knockout mice

The translocator protein, TSPO, has been implicated in a wide range of cellular processes exerted from its position in the outer mitochondrial membrane from where it influences lipid metabolism and mitochondrial oxidative activity. Understanding how this protein regulates a profusion of processes requires further elucidation and to that end we have examined lipid metabolism and used an RNAseq strategy to compare transcript abundance in wildtype and Tspo knockout (KO) mouse liver. The levels of cholesterol, triglyceride and phospholipid were significantly elevated in the KO mouse liver. The expression of cholesterol homeostasis genes was markedly downregulated. Determination of the differential expression revealed that many genes were either up- or downregulated in the KO animals. However, a striking observation within the results was a decrease of transcripts for protein degradation proteins in KO animals while protease inhibitors were enriched. When the entire abundance data-set was analysed with CEMiTool, and revealed a module of proteins that were under-represented in the KO animals. These could subsequently be formed into a network comprising three interlinked clusters at the centre of which were proteins of cytoplasmic ribosomes with gene ontology terms suggesting impairment to translation. The largest cluster was dominated by proteins of lipid metabolism but also contained disparate systems of iron metabolism and behaviour. The third cluster was dominated by proteins of the electron transport chain and oxidative phosphorylation. These findings suggest that TSPO contributes to lipid metabolism, detoxification of active oxygen species and oxidative phosphorylation, and regulates mitochondrial retrograde signalling.

An economically viable stable isotope-enhanced multiple reaction monitoring method for total fatty acid analysis in a mouse model of non-alcoholic fatty liver disease

The complex pathological mechanisms of non-alcoholic fatty liver disease (NAFLD) are closely related to dysregulated lipid metabolism, and the therapeutic effects of the traditional Chinese medicine Zexie-Baizhu Decoction (AA) on NAFLD have been gaining increasing attention. However, research into altered lipid metabolism, especially fatty acids, in NAFLD and the intervention of AA faces technical challenges, especially in the precise quantitative analysis of fatty acids in biological samples. The high complexity of biological matrices, particularly after drug intervention, greatly increases the difficulty of detection. Therefore, this study innovatively developed a simple and economical stable isotope derivatization technique by synthesizing d6N,N-dimethylethylenediamine (d6-DMED) in the laboratory, establishing a simple and economical method for fatty acid quantification. This method employs a chemical reaction under low-temperature conditions to ensure the efficient synthesis of d6-DMED. Using ultra-high performance liquid chromatography-triple quadrupole mass spectrometry technique (UHPLC-MS/MS), combined with optimized chromatographic separation conditions and dynamic multiple reaction monitoring mode, the study established a highly sensitive detection method for 35 fatty acid derivatives. Methodological evaluation showed that the limits of quantification ranged from 0.002 to 0.060 μM, with high linearity of R² > 0.995. Additionally, the relative recovery rates were between 93.14% and 106.63%. To further demonstrate the feasibility of this method for fatty acid quantification, it was applied to measure fatty acids in multiple tissues in a mouse NAFLD model, as well as the effects of AA intervention on fatty acid metabolism. This rapid, simple, and cost-effective detection method not only enhances the understanding of NAFLD mechanisms but also provides a new strategy for evaluating the biological complex system after drug intervention.

Sensitive Profiling of Mouse Liver Membrane Proteome Dysregulation Following a High-Fat and Alcohol Diet Treatment.

Alcohol consumption and high-fat (HF) diets often coincide in Western society, resulting in synergistic negative effects on liver function. Although studies have analyzed the global protein expression in the context of alcoholic liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease (MASLD), none has offered specific insights on liver dysregulation at the membrane proteome level. Membrane-specific profiling of metabolic and compensatory phenomena is usually overshadowed in conventional proteomic workflows. In this study, we use the Peptidisc method to isolate and compare the membrane protein (MP) content of the liver with its unique biological functions. From mice fed with an HF diet and ethanol in drinking water, we annotate over 1500 liver proteins with half predicted to have at least one transmembrane segment. Among them, we identify 106 integral MPs that are dysregulated compared to the untreated sample. Gene Ontology analysis reveals several dysregulated membrane-associated processes like lipid metabolism, cell adhesion, xenobiotic processing, and mitochondrial membrane formation. Pathways related to cholesterol and bile acid transport are also mutually affected, suggesting an adaptive mechanism to counter the upcoming steatosis of the liver model. Taken together, our Peptidisc-based profiling of the diet-dysregulated liver provides specific insights and hypotheses into the role of the transmembrane proteome in disease development, and flags desirable MPs for therapeutic and diagnostic targeting.

Astaxanthin Alleviates Hepatic Lipid Metabolic Dysregulation Induced by Microcystin-LR.

Microcystin-LR (MC-LR), frequently generated by cyanobacteria, has been demonstrated to raise the likelihood of liver disease. Few previous studies have explored the potential antagonist against MC-LR. Astaxanthin (ASX) has been shown to possess various beneficial effects in regulating lipid metabolism in the liver. However, whether ASX could alleviate MC-LR-induced hepatic lipid metabolic dysregulation is as yet unclear. In this work, the important roles and mechanisms of ASX in countering MC-LR-induced liver damage and lipid metabolic dysregulation were explored for the first time. The findings revealed that ASX not only prevented weight loss but also enhanced liver health after MC-LR exposure. Moreover, ASX effectively decreased triglyceride, total cholesterol, aspartate transaminase, and alanine aminotransferase contents in mice that were elevated by MC-LR. Histological observation showed that ASX significantly alleviated lipid accumulation and inflammation induced by MC-LR. Mechanically, ASX could significantly diminish the expression of genes responsible for lipid generation (Srebp-1c, Fasn, Cd36, Scd1, Dgat1, and Pparg), which probably reduced lipid accumulation induced by MC-LR. Analogously, MC-LR increased intracellular lipid deposition in THLE-3 cells, while ASX decreased these symptoms by down-regulating the expression of key genes in the lipid synthesis pathway. Our results implied that ASX played a crucial part in lipid synthesis and effectively alleviated MC-LR-induced lipid metabolism dysregulation. ASX might be developed as a novel protectant against hepatic impairment and lipid metabolic dysregulation associated with MC-LR. This study offers new insights for further management of MC-LR-related metabolic diseases.

Comparative Effects of Tumor Necrosis Factor Alpha, Lipopolysaccharide, and Palmitate on Mitochondrial Dysfunction in Cultured 3T3-L1 Adipocytes.

We have previously reported that dysregulated lipid metabolism and inflammation in 3T3-L1 adipocytes is attributed to tumor necrosis factor alpha (TNFα) rather than lipopolysaccharide (LPS) and palmitate (PA). In this study, we further compared the modulative effects of TNFα, LPS, and PA on mitochondrial function by treating 3T3-L1 adipocytes with TNFα (10 ng/mL), LPS (100 ng/mL), and PA (0.75 mM) individually or in combination for 24 h. Results showed a significant reduction in intracellular adenosine triphosphate (ATP) content, mitochondrial bioenergetics, total antioxidant capacity, and the mRNA expression of citrate synthase (Cs), sirtuin 3 (Sirt3), protein kinase AMP-activated catalytic subunit alpha 2 (Prkaa2), peroxisome proliferator-activated receptor gamma coactivator 1 alpha (Ppargc1α), nuclear respiratory factor 1 (Nrf1), and superoxide dismutase 1 (Sod1) in cells treated with TNFα individually or in combination with LPS and PA. Additionally, TNFα treatments decreased insulin receptor substrate 1 (Irs1), insulin receptor substrate 2 (Irs2), solute carrier family 2, facilitated glucose transporter member 4 (Slc2a4), and phosphoinositide 3 kinase regulatory subunit 1 (Pik3r1) mRNA expression. Treatment with LPS and PA alone, or in combination, did not affect the assessed metabolic parameters, while the combination of LPS and PA increased lipid peroxidation. These results show that TNFα but not LPS and PA dysregulate mitochondrial function, thus inducing oxidative stress and impaired insulin signaling in 3T3-L1 adipocytes. This suggests that TNFα treatment can be used as a basic in vitro model for studying the pathophysiology of mitochondrial dysfunction and related metabolic complications and screening potential anti-obesity therapeutics in 3T3-L1 adipocytes.

Targeting Gut Microbiota with Probiotics and Phenolic Compounds in the Treatment of Atherosclerosis: A Comprehensive Review.

Atherosclerosis (AS) is a chronic inflammatory vascular disease. Dysregulated lipid metabolism, oxidative stress, and inflammation are the major mechanisms implicated in the development of AS. In addition, evidence suggests that gut dysbiosis plays an important role in atherogenesis, and modulation of the gut microbiota with probiotics and phenolic compounds has emerged as a promising strategy for preventing and treating AS. It has been shown that probiotics and phenolic compounds can improve atherosclerosis-related parameters by improving lipid profile, oxidative stress, and inflammation. In addition, these compounds may modulate the diversity and composition of the gut microbiota and improve atherosclerosis. The studies evaluated in the present review showed that probiotics and phenolic compounds, when consumed individually, improved atherosclerosis by modulating the gut microbiota in various ways, such as decreasing gut permeability, decreasing TMAO and LPS levels, altering alpha and beta diversity, and increasing fecal bile acid loss. However, no study was found that evaluated the combined use of probiotics and phenolic compounds to improve atherosclerosis. The available literature highlights the synergistic potential between phenolic compounds and probiotics to improve their health-promoting properties and functionalities. This review aims to summarize the available evidence on the individual effects of probiotics and phenolic compounds on AS, while providing insights into the potential benefits of nutraceutical approaches using probiotic strains, quercetin, and resveratrol as potential adjuvant therapies for AS treatment through modulation of the gut microbiota.

The WFS1-ZnT3-Zn2+ Axis Regulates the Vicious Cycle of Obesity and Depression.

Obesity, a growing global health concern, is closely linked to depression. However, the neural mechanism of association between obesity and depression remains poorly understood. In this study, neural-specific WFS1 deficiency exacerbates the vicious cycle of obesity and depression in mice fed a high-fat diet (HFD), positioning WFS1 as a crucial factor in this cycle. Through human pluripotent stem cells (hESCs) neural differentiation, it is demonstrated that WFS1 regulates Zn2+ homeostasis and the apoptosis of neural progenitor cells (NPCs) and cerebral organoids by inhibiting the zinc transporter ZnT3 under the situation of dysregulated lipid metabolism. Notably, riluzole regulates ZnT3 expression to maintain zinc homeostasis and protect NPCs from lipotoxicity-induced cell death. Importantly, riluzole, a therapeutic molecule targeting the nervous system, in vivo administration prevents HFD-induced obesity and associated depression. Thus, a WFS1-ZnT3-Zn2+ axis critical is demonstrated for the vicious cycle of obesity and depression and that riluzole may have the potential to reverse this process against obesity and depression.

Degraded sweet corn cob polysaccharides modulate T2DM-induced abnormalities in hepatic lipid metabolism via the bile acid-related FXR-SHP and FXR-FGF15-FGFR4 pathways

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by dysregulation of glucose and lipid metabolism. This study aimed to elucidate the mechanism through which a degraded sweet corn cob polysaccharide (UE-DSCCP-A) mitigates T2DM by modulating hepatic lipid metabolism. Biochemical indices pertinent to lipid metabolism were assessed, and liver pathology was examined in T2DM mice following UE-DSCCP-A treatment. Additionally, metabolomics, PCR, and Western blot analyses were employed to investigate the underlying mechanisms involved. These findings indicated that UE-DSCCP-A ameliorated hepatic lipid metabolism disorders, decreased lipid accumulation, and mitigated hepatic fibrosis. Untargeted metabolomics analysis revealed that UE-DSCCP-A modulated pathways associated with steroid biosynthesis and bile acid synthesis and metabolism in T2DM mice. The bile acid assay results demonstrated that UE-DSCCP-A treatment reduced bile acid levels in both the serum and liver but increased fecal bile acid levels in T2DM mice. Furthermore, alterations in bile acid distribution within the liver were observed. UE-DSCCP-A has the capacity to activate the hepatic FXR-SHP pathway as well as the gut-liver axis involving FXR-FGF15-FGFR4 signaling. Consequently, UE-DSCCP-A is capable of modulating critical target genes and proteins associated with bile acid synthesis and metabolism, regulating steroid biosynthesis, and influencing bile acid synthesis and transport within the liver. Additionally, it has beneficial effects on lipid metabolism disorders in individuals with T2DM. Thus, UE-DSCCP-A represents a promising candidate for functional foods with inherent hypoglycemic properties.