Fatty Acid Metabolism Research Articles

Discovery of PPAR Alpha Lipid Pathway Modulators That Do Not Bind Directly to the Receptor as Potential Anti-Cancer Compounds

Peroxisome proliferator-activated receptors (PPARs) are considered good drug targets for breast cancer because of their involvement in fatty acid metabolism that induces cell proliferation. In this study, we used the KAIMRC1 breast cancer cell line. We showed that the PPARE-Luciferase reporter gets highly activated without adding any exogenous ligand when PPAR alpha is co-transfected, and the antagonist GW6471 can inhibit the activity. Using this reporter system, we screened 240 compounds representing kinase inhibitors, epigenetic modulators, and stem cell differentiators and identified compounds that inhibit the PPARα-activated PPARE-Luciferase reporter in the KAIMRC1 cell. We selected 11 compounds (five epigenetic modulators, two stem cell differentiators, and four kinase inhibitors) that inhibited the reporter by at least 40% compared to the controls (DMSO-treated cells). We tested them in a dose-dependent manner and measured the KAIMRC1 cell viability after 48 h. All 11 compounds induced the cell killing at different IC50 values. We selected two compounds, PHA665752 and NSC3852, to dissect how they kill KAIMRC1 cells compared to the antagonist GW6741. First, molecular docking and a TR-FRET PPARα binding assay showed that compared to GW6471, these two compounds could not bind to PPARα. This means they inhibit the PPARα pathway independently rather than binding to the receptor. We further confirmed that PHA665752 and NSC3852 induce cell killing depending on the level of PPARα expression, and as such, their potency for killing the SW620 colon cancer cell line that expresses the lowest level of PPARα was less potent than for the KAIMRC1 and MDA-MB-231 cell lines. Further, using an apoptosis array and fatty acid gene expression panel, we found that both compounds regulate the PPARα pathway by controlling the genes involved in the fatty acid oxidation process. Our findings suggest that these two compounds have opposite effects involving fatty acid oxidation in the KAIMRC1 breast cancer cell line. Although we do not fully understand their mechanism of action, our data provide new insights into the potential role of these compounds in targeting breast cancer cells.

Alterations in cardiac function correlate with a disruption in fatty acid metabolism in a mouse model of SMA.

Spinal Muscular Atrophy is an autosomal dominant disease caused by mutations and deletions within the SMN1 gene, with predominantly childhood onset. Although primarily a motor neuron disease, defects in non-neuronal tissues are described in both patients and mouse models. Here, we have undertaken a detailed study of the heart in the Smn2B/- mouse models of SMA, and reveal a thinning of the ventriclar walls as previously described in more severe mouse models of SMA. However most structural changes are resolved by accounting for the smaller body size of the SMA mouse, as was also confirmed in the SMN∆7 model. Echocardiography revealed increased systolic function, which was particularly pronounced in subsets of mice and an increase in global longitudinal strain, collectively indicative of increased cardiac stress in the Smn2B/- mouse model. We have used TMT proteomics to perform a longitudinal study of the proteome of the hearts of Smn2B/- mice and reveal a progressive dysregulation of LXR/RXR signalling which is a regulator of lipid metabolism. We further show consistent perturbations in lipid metabolism in the Smn2B/-, Smn-/-;SMN2;SmnΔ7and SmnΔ7/Δ7;SMN2 mouse models of SMA on the day of birth. This work indicates that although structural changes in the heart can be overstated by failing to account for body size, there are functional defects which could predispose the heart to subsequent failure. We identify a common molecular signature across mouse models pointing to a dysregulation in lipid metabolism, and suggest that manipulation of LXR/RXR signalling offers an opportunity to impact upon these pathways.

DNA Methylation and Transcriptome Profiling Reveal the Role of the Antioxidant Pathway and Lipid Metabolism in Plectropomus leopardus Skin Color Formation

Leopard coral grouper (Plectropomus leopardus), possessing a distinct red body color, is an important species in commercial markets; however, the high ratio of black individuals under intensive cultivation has limited the commercial value of the species. To dissect the regulatory mechanisms underlying the red skin trait in P. leopardus, gene expression and DNA methylation modifications were compared between red and black skin tissues after astaxanthin treatment. Astaxanthin effectively increased the redness value a* and body weight. Multi-omics analyses revealed the crucial roles of pathways related to antioxidants and lipid metabolism, particularly “Tyrosine metabolism”, “Melanogenesis”, “Fatty acid metabolism”, “Fatty acid elongation”, and “Biosynthesis of unsaturated acids”, in red skin coloration. A molecular network for the regulation of red skin coloration in P. leopardus was constructed, and pmel, tyr, tyrp1a, tyrp1b, dct, slc24a5, wnt1, acsl4, elovl1, elovl6l.1, elovl6l.2, and elovl7 were identified as key genes. Notably, pmel, acsl4, and elovl7 were negatively regulated by differential DNA methylation. Our results provide new insight into the molecular and epigenetic mechanisms of body color variation, representing a significant step towards breeding for the red skin trait in P. leopardus.

Spatially resolved transcriptomics reveals gene expression characteristics in uveal melanoma

PurposeUveal melanoma (UM) is the most common intraocular malignancy in adults. Previous studies have examined the intra-tumoral heterogeneity. However, the spatial distribution of tumor cells within the tumor microenvironment and its relationship with tumor progression still remains largely unclear. Our study aimed to analyze the correlation between cell distribution patterns and the prognosis of UM.MethodsIn this paper, we performed spatial transcriptomics (ST) sequencing on two UM samples to describe the different cellular distribution patterns. Gene Ontology (GO) and Kyoto Encyclopedia of Genes, Genomes (KEGG) functional enrichment analysis, and protein–protein interaction (PPI) network were performed to define the biological function of each cluster. Differentially expressed genes (DEGs) and survival analysis based on datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database further confirmed the correlation between cellular distribution and clinical prognosis.ResultsWe found two different patterns of tumor cell distribution. The focal tumor cells have a distinct ribosome synthesis and rRNA pathway. In contrast, the subpopulation tented to distribute diffusely was related to fatty acids metabolism profile, presumably supporting tumor growth by providing energy. The scattered tumor cell cluster was associated with malignant biological behaviors and was involved in extensive cellular interactions, including COLLAGEN. Moreover, pseudo-time analysis showed that migration started from the basal region through cell differentiation. According to the TCGA and GEO database, genes expressed characteristically in the scattered tumor cell cluster were related to poor prognosis.ConclusionsOur study drew the ST maps for UM for the first time. These findings revealed the distribution patterns of tumor cells associated with different biological functions and pointed towards specific tumor subpopulations with higher invasiveness as potential therapeutic targets. Together, our study displayed an overview of UM transcriptome and explored the intra-tumoral heterogeneity of UM at the spatial level.

Integrating single-cell RNA-Seq and bulk RNA-Seq data to explore the key role of fatty acid metabolism in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a predominant cause of cancer-related mortality globally, noted for its propensity towards late-stage diagnosis and scarcity of effective treatment modalities. The process of metabolic reprogramming, with a specific emphasis on lipid metabolism, is instrumental in the progression of HCC. Nevertheless, the precise mechanisms through which lipid metabolism impacts HCC and its viability as a therapeutic target have yet to be fully elucidated. In the current investigation, single-cell RNA sequencing in conjunction with weighted gene co-expression network analysis (WGCNA) was utilized to delineate lipid metabolism-related genes correlated with the prognostic outcomes of hepatocellular carcinoma (HCC). Data procurement encompassed transcriptomic and clinical datasets from HCC patients, sourced from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) repositories. Subsequent to this, consensus clustering analysis was implemented to stratify patients into distinct subgroups, contingent upon the expression patterns of lipid metabolism genes. Further analytical procedures involved functional enrichment analysis, evaluation of immune infiltration, and examination of the mutation landscape.PTGES3 was identified as a pivotal gene associated with lipid metabolism. Subsequent to its identification, cellular communication analysis was employed to assess the immunological attributes of PTGES3 within the tumor microenvironment. The functional role of PTGES3 was further corroborated through molecular docking simulations and in vitro experimental assays. We identified 27 genes associated with lipid metabolism, 18 of which exhibited significant correlation with overall survival in HCC patients. PTGES3 emerged as a central gene, demonstrating a robust association with immune cell infiltration and unfavorable prognosis. Cellular communication analysis revealed that PTGES3 exhibits the highest communication intensity with T cells, modulating the tumor microenvironment by potentiating the FN1/CD44 + MDK/NCL signaling pathway. Elevated expression of PTGES3 was linked to immunosuppressive cascades, diminished responsiveness to immunotherapy, and inferior overall survival outcomes. Molecular docking analysis indicated that etoposide, methotrexate, and doxorubicin could effectively bind to PTGES3. In vitro experiments confirmed that PTGES3 knockdown significantly impaired the proliferation, invasion, and migration of HCC cells. This study highlights the pivotal role of lipid metabolism in HCC progression and identifies PTGES3 as a potential prognostic biomarker and therapeutic target. These findings offer new insights into the development of targeted therapies for HCC, particularly in patients with high PTGES3 expression.

Comparative analysis of the whole transcriptome landscapes of muscle and adipose tissue in Qinchuan beef cattle

BackgroundMuscle and adipose tissue are the most critical indicators of beef quality, and their development and function are regulated by noncoding RNAs (ncRNAs). However, the differential regulatory mechanisms of ncRNAs in muscle and adipose tissue remain unclear.ResultsIn this study, 2,343 differentially expressed mRNAs (DEMs), 235 differentially expressed lncRNAs (DELs), 95 differentially expressed circRNAs (DECs) and 54 differentially expressed miRNAs (DEmiRs) were identified in longissimus dorsi muscle (LD), subcutaneous fat (SF) and perirenal fat (VF) in Qinchuan beef cattle. The results of functional enrichment analysis showed that DEMs, DELs, DECs and DEmiRs were enriched in biological processes related to development and function of muscle and fat deposition, including skeletal muscle contraction, muscle organ development, PPAR signaling pathway, fatty acid metabolism and MAPK signaling pathway. Based on the competing endogenous RNA (ceRNA) regulatory mechanism, we constructed a lncRNA/circRNA-miRNA-mRNA network consisting of 6 circRNAs, 5 lncRNAs, 6 miRNAs and 27 mRNAs. Among them, 55 ceRNA axes were involved, including circRNA12990 - bta-miR-133a_L-1R + 1 - MYO6/ZEB2, circRNA2893/MSTRG.28538.1/MSTRG.11613.4 - pma-miR-145-5p_R + 2 - EYA4 and MSTRG.26982.1 - bta-let-7e_R + 1 - RBM40.ConclusionsThis study identified a group of differentially expressed mRNAs, lncRNAs, circRNAs and miRNAs between muscle and adipose tissue and constructed a potential ceRNA regulatory network, which may serve as a foundation for studying the differential regulatory roles of ncRNAs in the development and function of muscle and adipose tissue.

Enhancing Cannabichromenic Acid Biosynthesis in Saccharomyces cerevisiae.

Cannabichromene (CBC), a valuable but extremely low-abundance component of cannabinoids in Cannabis sativa L., is known for its ability to promote neurogenesis. The scarcity of CBC in natural C. sativa is primarily attributed to the inefficiency of the 1-deoxy-D-xylulose 5-phosphate/2-C-methyl-D-erythritol 4 phosphate (DOXP/MEP) and fatty acid metabolism pathways, along with the limited competitive advantage of cannabichromenic acid synthetase (CBCAS) compared to other cannabinoid synthases. In this study, we constructed Saccharomyces cerevisiae capable of biosynthesizing cannabichromenic acid (CBCA) from glucose and olivetolic acid. First, we enhanced the supply of the precursor isopentenyl diphosphate/dimethylallyl diphosphate by introducing a two-step isopentenol utilization pathway (IUP). Additionally, we increased the CBCA titer by co-overexpressing endoplasmic reticulum auxiliary protein genes. Moreover, we improved the selectivity and catalytic activity of CBCAS through rational design. By localizing the IUP to peroxisomes, geranylgeranyl pyrophosphate and CBCA titers were further increased by 1.6-fold and 28%, respectively. Notably, the yeast strain synthesized CBCA at a rate 25.8% higher than that of C. sativa. Our findings suggest that microbial synthesis offers a promising alternative to traditional C. sativa for sustainable CBCA production.

2-[18F]Fluoropropionic Acid PET Imaging of Doxorubicin-Induced Cardiotoxicity.

Treatment of pediatric cancers with doxorubicin is a common and predictable cause of cardiomyopathy. Early diagnosis of treatment-induced cardiotoxicity and intervention are major determinants for the prevention of advanced disease. The onset of cardiomyopathies is often accompanied by profound changes in lipid metabolism, including an enhanced uptake of short-chain fatty acids (SCFA). Therefore, we explored the utility of 2-[18F]fluoropropionic acid ([18F]FPA), an SCFA analog, as an imaging biomarker of cardiac injury in mice exposed to doxorubicin. Cardiotoxicity and cardiac dysfunction were induced in mice by an 8-dose regimen of doxorubicin (cumulative dose 24mg/kg) administered over 14days. The effects of doxorubicin exposure were assessed by measurement of heart weights, left ventricular ejection fractions, and blood cardiac troponin levels. Whole body and cardiac [18F]FPA uptakes were determined by PET and tissue gamma counting in the presence or absence of AZD3965, a pharmacological inhibitor of monocarboxylate transporter 1 (MCT1). Radiation absorbed doses were estimated using tissue time-activity concentrations. Significantly higher cardiac [18F]FPA uptake was observed in doxorubicin-treated animals. This uptake remained constant from 30 to 120min post-injection. Pharmacological inhibition of MCT1-mediated transport by AZD3965 selectively decreased the uptake of [18F]FPA in tissues other than the heart. Co-administration of [18F]FPA and AZD3965 enhanced the imaging contrast of the diseased heart while reducing overall exposure to radioactivity. [18F]FPA, especially when co-administered with AZD3965, is a new tool for imaging changes in fatty acid metabolism occurring in response to doxorubicin-induced cardiomyopathy by PET.

Integrated transcriptome and metabolome analysis of liver reveals unsynchronized growth mechanisms in blunt-snout bream (Megalobrama amblycephala)

BackgroundMegalobrama amblycephala presents unsynchronized growth, which affects its productivity and profitability. The liver is essential for substance exchange and energy metabolism, significantly influencing the growth of fish.ResultsTo investigate the differential metabolites and genes governing growth, and understand the mechanism underlying their unsynchronized growth, we conducted comprehensive transcriptomic and metabolomic analyses of liver from fast-growing (FG) and slow-growing (SG) M. amblycephala individuals. A total of 2,097 differentially expressed genes (DEGs) were identified between FG and SG, with 830 genes exhibiting significantly higher expression level in FG. KEGG and GO enrichment analysis indicated that the DEGs with higher expression level were significantly correlated with insulin signaling pathway, steroid hormone and lipid metabolism related pathway (PPAR signaling pathway and fatty acid degradation). In the metabolomic analysis, 224 differentially expressed metabolites (DEMs) were detected, of which 128 were significantly more abundant in FG. These more abundant DEMs were prominently enriched in pathways associated with cell proliferation and energy metabolism (Oxidative phosphorylation, mTOR signaling pathway and FoxO signaling pathway). In addition, DEGs and DEMs in adenosine diphosphate (ATP) hydrolysis activity and associate with fatty acid metabolism, glucose metabolism, and amino acid metabolism pathways were both found in the transcriptomic and metabolomic integrated data. These findings suggest that the large amounts of energy generated by fatty acid, glucose metabolism and other energy metabolism pathway promote the rapid growth of FG.ConclusionsThis research is the first to integrate metabolomic and transcriptomic analyses of liver to identify key genes, metabolites, and pathways to uncover the molecular and metabolic mechanisms of unsynchronized growth in M. amblycephala. The identified metabolic and genes can be potential targets for selective breeding programs to improve growth performance in aquaculture.

Clonorchis sinensis Promotes Intrahepatic Cholangiocarcinoma Progression by Activating FASN-Mediated Fatty Acid Metabolism.

Clonorchis sinensis infection is an important risk factor for intrahepatic cholangiocarcinoma (ICC). C. sinensis positive (C.s+) ICC patients had much shorter overall survival (OS) compared with C. sinensis negative (C.s-) group. This study aims to explore the impact and underlying mechanism of C. sinensis infection on ICC progression. In this study, ICC patients underwent surgery from two medical centers enrolled. RNA sequencing was used to determine the downstream activated pathways and genes. Furthermore, we demonstrated the potential mechanism of C. sinensis infection in promoting ICC progression through invitro co culture systems and two animal models. Through RNA sequencing, we found fatty acid metabolism and the expression of fatty acid synthase (FASN), a key enzyme catalyzing long-chain fatty acid synthesis, were significantly elevated in C.s+ ICCs. Then, we found excretory/secretory products (ESPs) secreted by C. sinensis could significantly upregulate the expression of transcription factor E2F1, thereby promoting FASN expression and fatty acid synthesis in tumor cells, which ultimately accelerating tumor progression. However, the promotive effect disappeared when FASN was knocked down. Meanwhile, ESPs could promote tumor growth, increasing FASN expression and free fatty acid level in both subcutaneous and orthotopic mouse models. This study indicates that C. sinensis infection could upregulate the level of FASN and activate fatty acid synthesis pathway, thereby accelerating ICC progression. This provides a new insight for the clinical treatment of ICC with C. sinensis infection.

Comparative Analysis of γ-Cyclodextrin, Perilla Oil, and Their Inclusion Complexes on Liver Injury and Dyslipidemia Associated with Elevated Gastrointestinal 12-Hydroxylated Bile Acid Levels

Our previous study demonstrated that γ-cyclodextrin (γ-CD)–perilla oil inclusion complexes increase plasma α-linolenic acid and eicosapentaenoic acid levels in healthy rats without adverse effects. The present study examined the effects of perilla oil, γ-CD, and their inclusion complexes on rats fed cholic acid (CA) to mimic the elevated gastrointestinal 12-hydroxylated (12OH) bile acid levels in high-fat diet-fed rats. Rats fed CA (CA group) tended to have higher AST, ALT, plasma total cholesterol (T-CHO), and triglyceride (TG) levels compared to controls fed a standard diet without CA. Rats fed CA and perilla oil (CA+LP group) showed a tendency for lower AST and plasma TG levels than those in the CA group. Rats fed CA and γ-CD (CA+CD group) had significantly higher AST, ALT, plasma T-CHO, and TG levels than the controls, indicating severe liver injury and dyslipidemia. Rats fed CA and the γ-CD–perilla oil inclusion complex (CA+IC group) had significantly lower AST and ALT levels than the CA+CD rats, with a trend towards lower plasma T-CHO and TG levels. Plasma α-linolenic acid and eicosapentaenoic acid levels were significantly higher in the CA+LP and CA+IC groups than in the controls and CA+CD groups. However, the CA+IC group tended to have lower α-linolenic acid levels and significantly lower eicosapentaenoic acid levels than the CA+LP group. This suggests an accelerated conversion of α-linolenic acid to eicosapentaenoic acid in the CA+IC group, which may contribute to the attenuation of liver injury and dyslipidemia. These findings suggest that γ-CD may exacerbate liver injury and dyslipidemia caused by elevated gastrointestinal 12OH bile acid levels, whereas γ-CD–perilla oil inclusion complexes may ameliorate these effects by altering fatty acid metabolism. Furthermore, we recommend evaluating γ-CD safety in both healthy and pathological models and carefully selecting compounds co-ingested with γ-CD.

Exploring the role of ELOVLs family in lung adenocarcinoma based on bioinformatic analysis and experimental validation

BackgroundThe role of lipid metabolic reprogramming in the development of various types of cancer has already been established. However, the exact biological function and significance of the elongation of very-long-chain fatty acids (ELOVLs) gene family, which can affect fatty acid metabolism, is still not well understood in lung adenocarcinoma (LUAD). The aim of our study is to explore whether there are genes related to the pathogenesis of LUAD in the ELOVLs family, and even to guide clinical medication and potential prognostic indicators.MethodsGene expression profiling interactive analysis (GEPIA), human protein atlas (HPA), cBioPortal, Kaplan–Meier (KM) plotter, single-sample Gene Set Enrichment Analysis (ssGSEA) algorithm and SubMap algorithms were utilized to analyze the role of ELOVLs in the LUAD. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis, cell counting kit-8 (CCK8), colony formation, wound healing, transwell migration assays and fatty acid metabolism detection were employed to confirm the significant role of ELOVL6 in vitro experiment.ResultsOur results revealed that mRNA expression levels of ELOVL2, ELOVL4 and ELOVL6 and protein expression levels of ELOVL5 and ELOVL6 were elevated in LUAD tissues compared to normal subjects. The low-expressing ELOVL6 group showed superior overall survival (OS) and disease-specific survival (DSS) versus the high-expressing group. Meanwhile, patients with low-ELOVL6 expression were more sensitive to the 4 representative chemotherapeutic agents. In vitro, we revealed that interfering with ELOVL6 could influence the viability, proliferation, migration capacity and fatty acid metabolism of LUAD cells (A549 and H1299).ConclusionsOur study indicated that ELOVL6 could be used as an indicator to evaluate the prognosis and therapeutic effect, and even potential therapeutic target for patients with LUAD.

The associations between prenatal plastic phthalate exposure and lipid acylcarnitine levels in humans and mice.

Phthalates are ubiquitous environmental pollutants known for their endocrine-disrupting properties, particularly during critical periods such as pregnancy and early childhood. Phthalates alter lipid metabolism, but the role of prenatal exposure on the offspring lipidome is less understood. In particular, we focused on long chain acylcarnitines - intermediates of fatty acid oxidation that serve as potential biomarkers of mitochondrial function and energy metabolism. This study aimed (i) to investigate the association between prenatal phthalate exposure and the child's blood acylcarnitine concentrations and, (ii) to evaluate the impact of prenatal administration of di-(2-ethylhexyl) phthalate (DEHP) on acylcarnitine levels in mouse offspring blood, brain and liver. We conducted analyses of both a prospective birth cohort study and an experimental study in mice. From the Barwon Infant Study cohort (1074 mother-child pairs), prenatal phthalate exposure was assessed at 36 weeks' gestation and its association with acylcarnitine levels was examined in cord blood, and child's blood at 6 months, 12 months and 4 years. In mice, pregnant C57BL/6J mouse dams were exposed to 20μg/kg DEHP for 5 days mid-gestation, and offspring tissues were analyzed at 1 month of age postnatally for acylcarnitine profiles. Our findings demonstrate that prenatal phthalate levels (specifically butyl benzyl phthalate (BBzP) and diisobutyl phthalate (DiBP)) are inversely associated with total long chain acylcarnitine levels in human cord blood at birth. In contrast, BBzP was positively associated with the long chain acylcarnitines at 12 months of age. In mice, prenatal DEHP exposure for only 5 days led to decreased palmitoylcarnitine (AC16:0) levels in the brain and liver, but not in blood. Taken together, our findings highlight that prenatal phthalate exposure can alter acylcarnitine profiles, indicating disruptions in fatty acid metabolism that may have long-term effects on metabolic health.

Exploration of Novel Metabolic Mechanisms Underlying Primary Biliary Cholangitis Using Hepatic Metabolomics, Lipidomics, and Proteomics Analysis.

Metabolic reprogramming is important in primary biliary cholangitis (PBC) development. However, studies investigating the metabolic signature within the liver of PBC patients are limited. In this study, liver biopsies from 31 PBC patients and 15 healthy controls were collected, and comprehensive metabolomics, lipidomics, and proteomics analysis were conducted to characterize the metabolic landscape in PBC. We observed distinct lipidome remodeling in PBC with increased polyunsaturated fatty acid levels and augmented fatty acid β-oxidation (FAO), evidenced by the increased acylcarnitine levels and upregulated expression of proteins involved in FAO. Notably, PBC patients exhibited an increase in glucose-6-phosphate (G6P) and purines, alongside a reduction in pyruvate, suggesting impaired glycolysis and increased purines biosynthesis in PBC. Additionally, the accumulation of bile acids as well as a decrease in branched chain amino acids and aromatic amino acids were observed in PBC liver. We also observed an aberrant upregulation of proteins associated with ductular reaction, apoptosis, and autophagy. In conclusion, our study highlighted substantial metabolic reprogramming in glycolysis, fatty acid metabolism, and purine biosynthesis, coupled with aberrant upregulation of proteins associated with apoptosis and autophagy in PBC patients. Targeting the specific metabolic reprogramming may offer potential targets for the therapeutic intervention of PBC.

AMPK-Mediated Multi-Organ Protective Effects of GLP-1 Receptor Agonists

Review AMPK-Mediated Multi-Organ Protective Effects of GLP-1 Receptor Agonists Xin Wang 1 and Linxi Wang 2,* 1 Emergency Department, Fujian Medical University Union Hospital, Fuzhou 350001, China 2 Department of Endocrinology and Metabolism, Fujian Institute of Endocrinology, Fujian Medical University Union Hospital, Fuzhou 350001, China * Correspondence: dr.linxi.wang@foxmail.com Received: 11 October 2024; Revised: 23 October 2024; Accepted: 20 December 2024; Published: 9 January 2025 Abstract: AMP-activated protein kinase (AMPK) is a key enzyme broadly involved in regulating cellular metabolism, often called an “energy sensor”. Activated AMPK promotes ATP production and storage within cells, primarily by inhibiting ATP-consuming anabolic processes (such as protein, lipid, and ribosomal synthesis) and initiating ATP-producing catabolic pathways (such as fatty acid oxidation and glycolysis) to maintain energy homeostasis. AMPK regulates metabolic processes in various peripheral tissues, including glucose and lipid metabolism, cholesterol metabolism, and fatty acid and protein metabolism in pancreatic β-cells, the cardiovascular system, liver, kidneys, skeletal muscles, and the central nervous system. As an antidiabetic drug, the multi-organ protective effects of Glucagon-like peptide-1 receptor agonists (GLP-1RA) are increasingly being recognized. This paper reviews the mechanisms by which GLP-1RA confers organ protection via the AMPK signaling pathway.

SREBF1 facilitates pathological retinal neovascularization by reprogramming the fatty acid metabolism of endothelial cells.

Retinopathy of prematurity (ROP) is a proliferative retinal vascular disorder that critically affects the visual development of premature infants, potentially leading to irreversible vision loss or even blindness. Despite its significance, the underlying mechanisms of this disease remain insufficiently understood. In this study, we utilized the oxygen-induced retinopathy (OIR) mouse model and conducted endothelial functional assays to explore the role of Sterol Regulatory Element-Binding Protein 1 (SREBF1) in ROP pathogenesis. SREBF1 expression levels, along with its downstream targets, were investigated through Western blotting, RT-qPCR, and immunofluorescence staining techniques. Furthermore, Co-Immunoprecipitation (Co-IP) was employed to examine the molecular mechanisms involved. Our results demonstrated a significant increase in SREBF1 expression in both the OIR mouse model and hypoxic primary human retinal microvascular endothelial cells (HRMECs). Interventions conducted both in vivo and in vitro showed notable efficacy in reducing pathological neovascularization. Importantly, we discovered that SREBF1 plays a key role in modulating lipid metabolism in HRMECs by regulating the expression of ACC1 and FASN, leading to cellular reprogramming. This reprogramming influences HRMEC proliferation, migration, and tube formation through the HIF-1α/TGF-β signaling pathway, ultimately contributing to pathological retinal neovascularization. These findings provide new insights into the role of SREBF1 in angiogenesis within the context of ROP, offering potential therapeutic targets for the management and treatment of this disease.

Non-canonical hepatic androgen receptor mediates glucagon sensitivity in female mice through the PGC1α/ERRα/mitochondria axis.

Glucagon has recently been found to modulate liver fat content, in addition to its role in regulating gluconeogenesis. However, the precise mechanisms by which glucagon signaling synchronizes glucose and lipid metabolism in the liver remain poorly understood. By employing chemical and genetic approaches, we demonstrate that inhibiting the androgen receptor (AR) impairs the ability of glucagon to stimulate gluconeogenesis and lipid catabolism in primary hepatocytes and female mice. Notably, AR expression in the liver of female mice is up to three times higher than that in their male littermates, accounting for the more pronounced response to glucagon in females. Mechanistically, hepatic AR promotes energy metabolism and enhances lipid breakdown for liver glucose production in response to glucagon treatment through the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α)/estrogen-related receptor alpha (ERRα)-mitochondria axis. Overall, our findings highlight the crucial role of hepatic AR in mediating glucagon signaling and the sexual dimorphism in hepatic glucagon sensitivity.

Decanoylcarnitine improves liver mitochondrial dysfunction in hepatitis B virus infection by enhancing fatty acid β-oxidation.

The incidence of metabolic-associated steatotic liver disease in patients with chronic hepatitis B is increasing annually; however, the interaction between hepatitis B virus (HBV) infection and lipid metabolism remains unclear. This study attempted to clarify whether fatty acid metabolism regulation could alleviate mitochondrial dysfunction caused by HBV infection. Public gene set of human livers was analyzed, and a proteomic analysis on mouse livers was conducted to explore metabolic disorders and affected organelles associated with HBV infection. The effect of decanoylcarnitine on fatty acid β-oxidation and mitochondria was investigated in vivo and in vitro. The pathways involved were shown by proteomic analysis and confirmed by Western blot. HBV infection could cause fatty acid β-oxidation disorder and mitochondrial dysfunction in vivo and in vitro. CPT1A overexpression could improve mitochondrial function in hepatocytes. Furthermore, decanoylcarnitine supplementation could activate CPT1A expression, thus improving fatty acid metabolism and repairing mitochondrial dysfunction. Proteomic analysis of mouse livers suggests that decanoylcarnitine stimulates the peroxisome proliferator-activated receptor (PPAR) signaling pathway, and the PPARα was the most important among PPARs. Impaired fatty acid metabolism and mitochondrial dysfunction in hepatocytes caused by HBV infection could be partially restored by exogenous supplementation of decanoylcarnitine. It elucidated the therapeutic potential of decanoylcarnitine in HBV infection and provided a new approach for diseases related to mitochondrial dysfunction.

A novel human specific lncRNA MEK6-AS1 regulates adipogenesis and fatty acid biosynthesis by stabilizing MEK6 mRNA

BackgroundObesity is becoming one of the major non-communicable diseases with increasing incidence and risks that cannot be ignored. However effective and safe clinical treatment strategies still need to be deeply explored. Increased number and volume of adipocytes lead to overweight and obesity. The aim of our work is to identify lncRNAs that have important regulatory in differentiation of human mesenchymal stem cells (MSCs) into adipocytes, and to provide effective targets for clinical prevention and treatment of obesity and related metabolic disorders.MethodsWe extracted primary MSCs from human adipose tissue, and conducted expression profile analysis of lncRNAs during adipogenic differentiation of MSCs to screen changed lncRNAs. Characteristics of lncRNA were revealed mainly by RACE and RNA FISH. Loss- and gain-of function experiments in vivo and in vitro were used to analyze effects of lncRNA. Targeted metabolomics was utilized to detect levels of free fatty acids. RNA pull-down, mRNA stability tests, etc. were employed to explore mechanisms of lncRNA.ResultsHuman-specific lncRNA, we named it MEK6-AS1, was the most up-regulated transcript during adipogenic differentiation of MSCs. MEK6-AS1 was highly expressed in adipose tissue samples from individuals with BMI ≥ 25 and positively correlated with adipogenic marker genes in these samples. Knocking down lncRNA inhibited expression of adipogenic differentiation markers and ectopic adipogenesis, reducing contents of various free fatty acids, as well as promoting osteogenic differentiation. Overexpression of lncRNA had the opposite effects to the above processes. We also found that MEK6-AS1 was elevated during hepatic steatosis organoid generation. Mechanistically, MEK6-AS1 worked partially through stabilization of MEK6 mRNA by NAT10.ConclusionsWe have identified a human-specific lncRNA (MEK6-AS1) with position information in the genomic database but has not been extensively reported. We demonstrated that MEK6-AS1 as a novel lncRNA involved in adipogenic differentiation and adipogenesis, fatty acid metabolism, and osteogenic differentiation. We found that MEK6-AS1 may exert its effect by enhancing MEK6 mRNA stability through NAT10. Our study may provide insights into implication of lncRNAs in stem cell biology and offer a new potential therapeutic target for the prevention and treatment of obesity and other related disease.

Antifungal Activity of Genistein Against Phytopathogenic Fungi Valsa mali Through ROS-Mediated Lipid Peroxidation.

Valsa mali (V. mali) is a necrotrophic fungus responsible for apple Valsa canker, which significantly diminishes apple production yields and quality in China. Our serendipitous findings revealed that genistein significantly inhibits the mycelial growth of V. mali, with an inhibition rate reaching 42.36 ± 3.22% at a concentration of 10 µg/mL. Scanning electron microscopy analysis revealed that genistein caused significant changes in the structure of V. mali, including mycelial contraction, distortion, deformity, collapse, and irregular protrusions. Transmission electron microscopy analysis revealed leakage of cellular contents, blurred cell walls, ruptured membranes, and organelle abnormalities. Genistein has been shown to increase reactive oxygen species levels in V. mali mycelia, as demonstrated by 2',7'-dichlorofluorescin diacetate staining. This increase was associated with a decrease in superoxide dismutase activity alongside increases in catalase and peroxidase activities. These changes collectively disrupted the oxidative equilibrium, leading to the induction of oxidative stress. The transcriptomic analysis revealed 13 genes enriched in this process, linked to unsaturated fatty acid biosynthesis (three downregulated DEGs), saturated fatty acid biosynthesis (three upregulated and six downregulated DEGs), and fatty acid metabolism (four upregulated and nine downregulated DEGs). Additionally, the downregulated DEGs VMIG_07417 and VMIG_08675, which are linked to ergosterol biosynthesis, indicate possible changes in membrane composition. In conjunction with the qRT-PCR results, it is hypothesized that genistein exerts an antifungal effect on V. mali through ROS-mediated lipid peroxidation. This finding has the potential to contribute to the development of novel biological control agents for industrial crops.