Key Enzyme In Lipid Metabolism Research Articles

SIRT2-mediated deacetylation of ACLY promotes the progression of oesophageal squamous cell carcinoma.

ATP citrate lyase (ACLY), as a key enzyme in lipid metabolism, plays an important role in energy metabolism and lipid biosynthesis of a variety of tumours. Many studies have shown that ACLY is highly expressed in various tumours, and its pharmacological or gene inhibition significantly inhibits tumour growth and progression. However, the roles of ACLY in oesophageal squamous cell carcinoma (ESCC) remain unclear. Here, our data showed that ACLY inhibitor significantly attenuated cell proliferation, migration, invasion and lipid synthesis in different ESCC cell lines, whereas the proliferation, migration, invasion and lipid synthesis of ESCC cells were enhanced after ACLY overexpression. Furthermore, ACLY inhibitor dramatically suppressed tumour growth and lipid metabolism in ESCC cells xenografted tumour model, whereas ACLY overexpression displayed the opposite effect. Mechanistically, ACLY protein harboured acetylated modification and interacted with SIRT2 protein in ESCC cells. The SIRT2 inhibitor AGK2 significantly increased the acetylation level of ACLY protein and inhibited the proliferation and migration of ESCC cells, while overexpression of ACLY partially reversed the inhibitory effect of AGK2 on ESCC cells. Overall, these results suggest that targeting the SIRT2/ACLY signalling axis may be a potential therapeutic strategy for ESCC patients.

Small molecule inhibitor azd1480 reverses radiotherapy resistance in NSCLC by targeting JAK2/STAT3 pathway

Purpose: To investigate the effect of small molecule inhibitor AZD1480 on radiotherapy resistance in non-small cell lung cancer (NSCLC), and the involvement of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway in the process.
 Methods: Radiation-resistant cell lines A549-20F, A549-30F, A549-40F and H460, H46040F, H460- 40F, and H460-40F were established, and expressions of proteins related to JAK/STAT pathway, mitogen-activated protein (MAPK) pathway and transforming growth factor-β (TGF- β) were assayed. The JAK2V617FH460 overexpression cell line and JAK2H460 cell line were established, and expressions of ATGL and CPT1A were compared. The H460 cells and H460-40F cells were treated with JAK2 small molecule inhibitor AZD1480, and the expressions of ATGL, CPT1A and JAK2/STAT3 pathway-related proteins were compared. The survival and proliferation of cell lines were also compared. 
 Results: The JAK/STAT pathway was significantly enriched, and MAPK and TGF-β were up-regulated. In H460 cells, JAK2/STAT3 route was obvious, suggesting that radiotherapy activated JAK2/STAT3 pathway in NSCLC cells. Significant down-regulations of p- JAK2Y1007, JAK2, p-STAT3s727, STAT3, ATGL and CPT1A proteins expressions were seen in H460 + AZD1480 group, relative to H460 group, but protein levels of p-JAK2Y1007, JAK2, p-STAT3s727, STAT3, ATGL and CPT1A were significantly lower in H460-40F + AZD1480 group than in H460-40F group (p < 0.05). The survival and proliferation rates were significantly lower in A549 + AZD1480 group than in A549 and A549-40F groups (p < 0.05).
 Conclusion: Radiotherapy up-regulates the expressions of ATGL and CPT1A in NSCLC cells by activating the JAK2/STAT3 pathway, while AZD1480, a small molecule inhibitor, reverses the radiation resistance of NSCLC by targeting JAK2/STAT3 pathway and key enzymes of lipid metabolism. Therefore, azd1480 may enhance clinical treatment efficacy in NSCLC patients by reducing radiation resistance.

Metabolic remodeling of visceral and subcutaneous white adipose tissue during reacclimation of rats after cold.

Deciphering lipid metabolism in white adipose tissue (WAT) depots during weight gain is important to understand the heterogeneity of WAT and its roles in obesity. Here, we examined the expression of key enzymes of lipid metabolism and changes in the morphology of representative visceral (epididymal) and subcutaneous (inguinal) WAT (eWAT and iWAT, respectively)-in adult male rats acclimated to cold (4 ± 1°C) for 45 days and reacclimated to room temperature (RT, 22 ± 1°C) for 1, 3, 7, 12, 21, or 45 days. The relative mass of both depots decreased to a similar extent after cold acclimation. However, fatty acid synthase (FAS), glucose-6-phosphate dehydrogenase (G6PDH), and medium-chain acyl-CoA dehydrogenase (ACADM) protein level increased only in eWAT, whereas adipose triglyceride lipase (ATGL) expression increased only in iWAT. During reacclimation, the relative mass of eWAT reached control values on day 12 and that of iWAT on day 45 of reacclimation. The faster recovery of eWAT mass is associated with higher expression of FAS, acetyl-CoA carboxylase (ACC), G6PDH, and ACADM during reacclimation and a delayed increase in ATGL. The absence of an increase in proliferating cell nuclear antigen suggests that the observed depot-specific mass increase is predominantly due to metabolic adjustments. In summary, this study shows a differential rate of visceral and subcutaneous adipose tissue weight regain during post-cold reacclimation of rats at RT. Faster recovery of the visceral WAT as compared to subcutaneous WAT during reacclimation at RT could be attributed to observed differences in the expression patterns of lipid metabolic enzymes.

Mitigation of Hepatic Impairment with Polysaccharides from Red Alga Albidum corallinum Supplementation through Promoting the Lipid Profile and Liver Homeostasis in Tebuconazole-Exposed Rats.

Sulfated polysaccharides from seaweed are highly active natural substances with valuable applications. In the present paper, attempts have been made to discuss the physicochemical and structural features of polysaccharides isolated from red marine alga Alsidium corallinum (ACPs) and their protective effect in hepatic impairments induced by tebuconazole (TEB) in male adult rats. Structural features were determined using high-performance liquid chromatography, Fourier-transformed infrared, and solid-state 1H and 13C-Nuclear magnetic resonance analysis. ACPs are found to be hetero-sulfated-anionic polysaccharides that contain carbohydrates, sulfate groups, and uronic acids. In vitro biological activities suggested the effective antioxidant and antimicrobial capacities of ACPs. For antioxidant testing in vivo, the biochemical analysis and plasma profiles displayed that oral administration of ACPs could mitigate blood lipid indicators, including total cholesterol, triglyceride, low and high-density lipoprotein cholesterol, and bilirubin. Liver function indexes involving alanine aminotransferase and aspartate aminotransferase showed that ACPs possessed prominent antioxidant activities. Additionally, the intervention of ACPs potentially inhibited lipid peroxidation, protein oxidation, key enzymes of lipid metabolism (<0.001), and improved antioxidant status (<0.05). Histomorphological observation confirmed that ACPs intervention could partially repair liver injuries caused by TEB. The computational results showed that A. corallinum monosaccharides bound 1JIJ, 1HD2, and 1WL4 receptors with acceptable affinities, which, together with deep embedding and molecular interactions, support the antioxidant, antimicrobial, and hypolipidemic outlined effects in the in vitro and in vivo findings. Given their prominent antioxidant effects, ACPs are promising candidates for liver diseases and must be considered in pharmaceutical applications.

Hypolipidemic Activity of Sesquiterpene Lactones and their Derivatives

BACKGROUND: Despite the available range of lipid-lowering drugs, mainly of synthetic origin, the problem of atherosclerosis therapy and its manifestations remain unresolved. Bioinformatics methods, in particular molecular docking, are considered as a promising direction in terms of developing effective original lipid-lowering drugs. Today, as a promising source of natural lipid-lowering agents, it is advisable to consider natural terpenoids, namely sesquiterpene lactones, which are distinguished by a wide range of pharmacological activity. This article presents the results of a virtual and biological screening of the lipid-lowering activity of sesquiterpene γ-lactones and their chemically modified derivatives. AIM: The aim is to evaluate the lipid-lowering properties of samples of sesquiterpene γ-lactones and their derivatives by virtual and biological screening methods. METHODS: Molecular modeling of the binding energy of the “ligand-target” complex (docking). Molecular docking of the lipid-lowering activity of sesquiterpene γ-lactones and their derivatives was performed using the Glide program from the developer of the Schrodinger Small-Molecule Drug Discovery package using the Extra Precision algorithm (https://www.schrodinger.com/glide). The effect of sesquiterpene lactones on the expression of genes for key enzymes of lipid metabolism in the liver was studied in an in vivo model of hyperlipidemia caused by an atherogenic diet. CONCLUSION: Virtual screening of the lipid-lowering activity of sesquiterpene γ-lactones and their derivatives by molecular docking revealed a number of promising compounds (matricin, matricarin, grossmisin oxime, austricin oxime, 5β (H)-austricin) receptor interactions on the enzyme system cholesterol 7α-hydroxylase (CYP7A1). New mechanisms of lipid-lowering activity for sesquiterpene γ-lactones were proposed, which were established in the study of gene expression of key enzymes of lipid metabolism in the liver in a model of hyperlipidemia caused by an atherogenic diet in rats under in vivo conditions.

Characteristics of Mycobacterium tuberculosis PtpA interaction and activity on the alpha subunit of human mitochondrial trifunctional protein, a key enzyme of lipid metabolism.

During Mycobacterium tuberculosis (Mtb) infection, the virulence factor PtpA belonging to the protein tyrosine phosphatase family is delivered into the cytosol of the macrophage. PtpA interacts with numerous eukaryotic proteins modulating phagosome maturation, innate immune response, apoptosis, and potentially host-lipid metabolism, as previously reported by our group. In vitro, the human trifunctional protein enzyme (hTFP) is a bona fide PtpA substrate, a key enzyme of mitochondrial β-oxidation of long-chain fatty acids, containing two alpha and two beta subunits arranged in a tetramer structure. Interestingly, it has been described that the alpha subunit of hTFP (ECHA, hTFPα) is no longer detected in mitochondria during macrophage infection with the virulent Mtb H37Rv. To better understand if PtpA could be the bacterial factor responsible for this effect, in the present work, we studied in-depth the PtpA activity and interaction with hTFPα. With this aim, we performed docking and in vitro dephosphorylation assays defining the P-Tyr-271 as the potential target of mycobacterial PtpA, a residue located in the helix-10 of hTFPα, previously described as relevant for its mitochondrial membrane localization and activity. Phylogenetic analysis showed that Tyr-271 is absent in TFPα of bacteria and is present in more complex eukaryotic organisms. These results suggest that this residue is a specific PtpA target, and its phosphorylation state is a way of regulating its subcellular localization. We also showed that phosphorylation of Tyr-271 can be catalyzed by Jak kinase. In addition, we found by molecular dynamics that PtpA and hTFPα form a stable protein complex through the PtpA active site, and we determined the dissociation equilibrium constant. Finally, a detailed study of PtpA interaction with ubiquitin, a reported PtpA activator, showed that additional factors are required to explain a ubiquitin-mediated activation of PtpA. Altogether, our results provide further evidence supporting that PtpA could be the bacterial factor that dephosphorylates hTFPα during infection, potentially affecting its mitochondrial localization or β-oxidation activity.

Stearoyl-CoA Desaturases1 Accelerates Non-Small Cell Lung Cancer Metastasis by Promoting Aromatase Expression to Improve Estrogen Synthesis.

Metastases contribute to the low survival rate of non-small cell lung cancer (NSCLC) patients. Targeting lipid metabolism for anticancer therapies is attractive. Accumulative evidence shows that stearoyl-CoA desaturases1 (SCD1), a key enzyme in lipid metabolism, enables tumor metastasis and the underlying mechanism remains unknown. In this study, immunohistochemical staining of 96 clinical specimens showed that the expression of SCD1 was increased in tumor tissues (p < 0.001). SCD1 knockdown reduced the migration and invasion of HCC827 and PC9 cells in transwell and wound healing assays. Aromatase (CYP19A1) knockdown eliminated cell migration and invasion caused by SCD1 overexpression. Western blotting assays demonstrated that CYP19A1, along with β-catenin protein levels, was reduced in SCD1 knocked-down cells, and estrogen concentration was reduced (p < 0.05) in cell culture medium measured by enzyme-linked immunosorbent assay. SCD1 overexpression preserving β-catenin protein stability was evaluated by coimmunoprecipitation and Western blotting. The SCD1 inhibitor A939572, and a potential SCD1 inhibitor, grape seed extract (GSE), significantly inhibited cell migration and invasion by blocking SCD1 and its downstream β-catenin, CYP19A1 expression, and estrogen concentration. In vivo tumor formation assay and a tail vein metastasis model indicated that knockdown of SCD1 blocked tumor growth and metastasis. In conclusion, SCD1 could accelerate metastasis by maintaining the protein stability of β-catenin and then promoting CYP19A1 transcription to improve estrogen synthesis. SCD1 is expected to be a promised therapeutic target, and its novel inhibitor, GSE, has great therapeutic potential in NSCLC.

Abstract 2690: In vivo CRISPR screen identifies SOAT1 as a chemotherapy chemosensitizing target for non-small cell lung cancer (NSCLC)

Abstract Purpose: To identify druggable gene targets that would sensitize NSCLCs to available chemotherapy agents. Experimental Procedures: We developed a CRISPR-Cas9 lentivirus library of 12,474 sgRNAs targeting 660 FDA proved ‘druggable’ putative proteins (18 guides/gene) and investigated their potential to chemosensitize (“drop out” in the presence of taxane) the NSCLC lung adenocarcinoma (LUAD) line NCI-H2009 (TP53 and KRAS mutant) in parallel studies in vitro (tissue culture) &amp; in vivo (xenografts). Key elements of our experiments were: the use low doses of paclitaxel (IC10 values for in vitro and in vivo doses that barely affected tumor growth) compared to control treatment; treatment schedules in vitro and in vivo that mirrored those used in patients; multiple biologic replicates for each transfection and drug selection; and large representation (2,000 cells/sgRNA) for each guide. At the end time point (1 month) we harvested multiple replicates of the taxane and control treatments and sequenced each to identify each guide that “remained” or “dropped out.” Data Summary: We were looking for guides that selectively dropped out in the setting of low dose taxane exposure comparing taxane to control treatment and in vitro to in vivo results. Of importance, we found little overlap between guides that dropped out during taxane exposure in tissue culture vs those that dropped out in xenografts. From the top 10 gene “sensitizers” that selectively dropped out only with taxane treatment and selectively dropped out in xenografts compared to 2D mass tissue culture, we focused on SOAT1 (Sterol O-Acyltransferase 1). SOAT1 is a key enzyme for lipid metabolism which mediates conversion of intracellular free cholesterol to cholesteryl esters which are then stored as lipid droplets. SOAT1 is a potential cancer therapeutic target with a clinically available inhibitor, avasimibe. H2009 cells with SOAT1 hemizygously removed (CRISPR) grew well in vitro and in vivo in the absence of chemotherapy treatment, but were dramatically sensitized to taxanes compared to parental H2009 cells. While avasimibe treatment, at concentrations achievable in patients, sensitized NSCLC to taxanes, this sensitization was not as dramatic as hemizygous removal by CRISPR. Of equal importance, SOAT1 H2009 hemizygous knockout (KO) cells were also dramatically sensitized to etoposide, pemetrexed, and gemcitabine, other chemotherapy agents used in NSCLC treatment. Mechanistically, RNAseq analysis identified G2/M cell cycle related gene sets as enriched in the H2009 SOAT1 KO xenografts compared to SOAT1 wildtype xenografts with paclitaxel treatment. Conclusions: Our results using CRISPR screening in vivo, identified SOAT1 as a critical therapeutic chemosensitizing target requiring only 50% inhibition of activity for sensitizing NSCLC to several chemotherapy agents routinely used in the clinic. Citation Format: Long Shan Li, Kenneth Huffman, Huiyu Li, Michael Peyton, Hyunsil Park, Kimberley Avila, Luc Girard, Mathew Augustine, Joshua T. Mendell, John D. Minna. In vivo CRISPR screen identifies SOAT1 as a chemotherapy chemosensitizing target for non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2690.

Leveraging Genetics to Address the Role of GALNT2 on Atherogenic Dyslipidemia.

Several studies have shown that downregulation of GALNT2(PolypeptideN-Acetylgalactosaminyltransferase2), encoding polypeptide N-acetylgalactosaminyltransferase 2, decreases high-density lipoprotein cholesterol (HDL-C) and increases triglycerides levels by glycosylating key enzymes of lipid metabolism, such as angiopoietin like 3, apolipoprotein C-III, and phospholipid transfer protein. GALNT2 is also a positive modulator of insulin signaling and action, associatedwith in vivo insulin sensitivity and during adipogenesis strongly upregulates adiponectin. Thus, the hypothesis that GALNT2 affects HDL-C and triglycerides levels also through insulin sensitivity and/or circulating adiponectin, is tested. In 881 normoglycemic individuals the G allele of rs4846914 SNP at theGALNT2 locus, known to associate with GALNT2 downregulation, is associated with low HDL-C and high values of triglycerides, triglycerides/HDL-C ratio, and theHomeostaticModelAssessmentofinsulin resistance HOMAIR (p-values = 0.01, 0.027, 0.002, and 0.016, respectively). Conversely, no association is observed with serum adiponectin levels (p= 0.091). Importantly, HOMAIR significantly mediates a proportion of the genetic association with HDL-C (21%, 95% CI: 7-35%, p= 0.004) and triglyceride levels (32%, 95% CI: 4-59%, p= 0.023). The results are compatible with the hypothesis that, besides the effect on key lipid metabolism enzymes, GALNT2 alters HDL-C and triglyceride levels also indirectly through a positive effect on insulin sensitivity.

Ginger polysaccharide promotes myeloid-derived suppressor cell apoptosis by regulating lipid metabolism.

Recently, targeting myeloid-derived suppressor cells (MDSCs) which mainly play an immunosuppressive role in tumor microenvironment has become a hot spot in tumor immunotherapy. This study focuses on biological effect of ginger polysaccharide extracted from natural plants on promoting apoptosis of MDSCs by regulating lipid metabolism. An MTT assay was used to detect the inhibitory effect of ginger polysaccharide on the growth of an MDSC-like cell line (MSC-2). The apoptosis-promoting effect of ginger polysaccharide on MSC-2 cells was detected by flow cytometry. Expression levels of apoptosis proteins (caspase 9 and Bcl-2) and lipid metabolism enzymes (fatty acid synthase (FASN) and diacylglycerol acyltransferase 2) in MSC-2 cells treated with different concentrations of ginger polysaccharide were detected by western blot assay. Nile red staining was used to quantitatively detect the effect of ginger polysaccharide on lipid droplet synthesis. Ginger polysaccharide inhibited proliferation of MSC-2 cells and promoted their apoptosis by upregulating pro-apoptotic caspase 9 protein, downregulating anti-apoptotic Bcl-2 protein, inhibiting expression of FASN and diacylglycerol acyltransferase 2 (key enzymes in fatty acid synthesis and lipid droplet formation, respectively). Ginger polysaccharide promoted apoptosis of MDSCs by regulating key lipid metabolism enzymes, inhibiting fatty acid synthesis and lipid droplet accumulation, and reducing the energy supply of cells.

Fatty acid-sensing mechanisms in the hypothalamus of European sea bass (Dicentrarchus labrax): The potential role of monounsaturated and polyunsaturated fatty acids

This study aimed to evaluate the hypothalamus fatty acid (FA)-sensing mechanisms response to different FA in European sea bass. For that purpose, fish (body weight of 90 g) were intraperitoneally (IP) injected (time 0 h) with five long-chain unsaturated fatty acids, namely, docosahexaenoic acid (DHA; C22:5n3); eicosapentaenoic acid (EPA; C20:4n3); α-linolenic (ALA; C18:3n3); linoleic acid (LA; C18:2n6) and oleic acid (OA; C18:1n9) at a dose of 300 μg kg−1, or with 0.9% saline solution (control). Feed intake (FI) was recorded at 3, 6, and 24 h after the IP injection. One week later, fish were IP injected with the same FA, and the hypothalamus was collected 3 h after the IP injection for measurement of molecules related to FI regulation and FA-sensing mechanisms. Cumulative FI (g/kg/day) was not affected by treatments. However, compared to the control, FI increased with the OA treatment at 6 h after the IP injection. FI decreased with mealtime in the DHA and LA groups. Gene expression of orexigenic (npy/agrp) and anorexigenic (cart2/pomc1) neurons was not affected by the FA treatments. Attending the enzymes involved in the FA-sensing mechanisms activation, compared to the control carnitine palmitoyltransferase I (CPT1) and ATP citrate lyase (ACLY) activity were not affected by FA treatments. Contrarily the key enzymes of lipid metabolisms, malic enzyme and hydroxyacylCoA dehydrogenase was higher in fish that received the EPA and OA treatment, than fish treated to the control. Overall, the results of the present study indicate that gene expression of orexigenic and anorexigenic neurons was not affected at 3 h after IP injection with different FA. However, the activity of key enzymes of lipid metabolism was differently affected by circulating FA, indicating that FA-sensing mechanisms respond to different FA. Further studies are required involving different sampling times to further characterize the response of FA-sensing mechanisms to FA. These findings may be of relevance to the aquaculture industry in an era where alternative lipid sources are being increasingly used.

In-Season Consumption of Locally Produced Tomatoes Decreases Cardiovascular Risk Indices

Tomatoes are widely consumed worldwide at any time of the year. However, depending on the variety, they have a characteristic season. We evaluated the consequences metabolic of consumption of Ekstasis tomatoes from different geographical origin and in different seasons in Fischer 344 rats. The hepatic gene expression of key enzymes in lipid metabolism was also evaluated. Animals were classified in three photoperiods (L6, L12, and L18) and in three treatments (vehicle: VH; local tomato: LT; and non-local tomato: nLT). We measured serum metabolic parameters and the gene expression of liver enzymes related to lipid metabolism (Acc1, Cpt1a, Had, Fas1, Srebp-1c, Fatp5, Cd36). LT consumption in season decreased cardiovascular risk 1 and coefficient atherogenic by 1.81 (p = 0.031) and in L6 decreased TAG and glucose (p = 0.046; p = 0.024). The L18-LT animals had decreased total cholesterol (p = 0.029) and gene expression of Srebp1-c (p = 0.022) but increased expression of Acc1 (p = 0.032). The treatments significantly affected the expression of Acc1 and Fas1 in the liver and the levels of serum TAG and glucose. A significant effect of photoperiod on serum concentration of glucose, insulin, HOMA index, and on the hepatic expression of Srep1-c, Fas1, and Acc1 was observed.

Fenofibrate suppresses corneal neovascularization by regulating lipid metabolism through PPARα signaling pathway.

Purpose: The purpose of this study was to explore the potential underlying mechanism of anti-vascular effects of peroxisome proliferator-activated receptor α (PPARα) agonist fenofibrate against corneal neovascularization (CNV) through the changes of lipid metabolism during CNV. Methods: A suture-induced CNV model was established and the clinical indications were evaluated from day 1 to day 7. Treatments of vehicle and fenofibrate were performed for 5days after suture and the CNV areas were compared among the groups. The eyeballs were collected for histological analysis, malondialdehyde (MDA) measurement, terminal deoxynucleotidyl transferase 2'-deoxyuridine 5'-triphosphate nick end labeling (TUNEL) staining, western blot, quantitative real-time PCR (qRT-PCR) assays and immunohistochemical (IHC) staining to elucidate pathological changes and the underlying mechanism. Results: Lipi-Green staining and MDA measurement showed that lipid deposition and peroxidation were increased in the CNV cornea while the expression of long-chain acyl-coenzyme A synthetase 1 (ACSL1), carnitine palmitoyltransterase 1A(CPT1A) and medium-chain acyl-coenzyme A dehydrogenase (ACADM), which are key enzymes of fatty acid β-oxidation (FAO) and targeted genes of peroxisome proliferator-activated receptor alpha (PPARα) pathway, were decreased in CNV cornea. Fenofibrate suppressed lipid accumulation and peroxidation damage in the CNV cornea. Fenofibrate upregulated the expression levels of PPARα, ACSL1, CPT1A, and ACADM compared with vehicle group. IHC staining indicated that fenofibrate also decreased the expression of VEGFa, VEGFc, TNFα, IL1β and CD68. Conclusion: Disorder of lipid metabolism may be involved in the formation of suture-induced CNV and fenofibrate played anti-neovascularization and anti-inflammatory roles on cornea by regulating the key enzymes of lipid metabolism and ameliorating lipid peroxidation damage of cornea through PPARα signaling pathway.

ABHD5-A Regulator of Lipid Metabolism Essential for Diverse Cellular Functions.

The α/β-Hydrolase domain-containing protein 5 (ABHD5; also known as comparative gene identification-58, or CGI-58) is the causative gene of the Chanarin-Dorfman syndrome (CDS), a disorder mainly characterized by systemic triacylglycerol accumulation and a severe defect in skin barrier function. The clinical phenotype of CDS patients and the characterization of global and tissue-specific ABHD5-deficient mouse strains have demonstrated that ABHD5 is a crucial regulator of lipid and energy homeostasis in various tissues. Although ABHD5 lacks intrinsic hydrolase activity, it functions as a co-activating enzyme of the patatin-like phospholipase domain-containing (PNPLA) protein family that is involved in triacylglycerol and glycerophospholipid, as well as sphingolipid and retinyl ester metabolism. Moreover, ABHD5 interacts with perilipins (PLINs) and fatty acid-binding proteins (FABPs), which are important regulators of lipid homeostasis in adipose and non-adipose tissues. This review focuses on the multifaceted role of ABHD5 in modulating the function of key enzymes in lipid metabolism.

Origin and evolution of fatty acid desaturase genes in oil crop Brassica napus

Fatty acid (FA) desaturases, as the key enzymes in lipid metabolism, are responsible for biosynthesis of the unsaturated fatty FAs, which play important roles in maintaining cell membrane integrity and multiple stress responses. Although attention has been drawn to some plant FA desaturase genes, their global landscape in oil crops is still lacking. Here, we performed systematic characterization and phylogenomic synteny network analyses of the FA desaturase gene family in polyploid oil crop B. napus and other 54 species covering major streptophyte lineages. A total of 1653 FA desaturase genes were identified from these plant genomes. Based on the broad-scale family phylogeny and functional domains, we proposed a unified eight-group classification system for angiosperm FA desaturases, and found that the origin of genes responsible for FA desaturation evolved early and some genes were absent in different species. Phylogenomic analyses revealed deeply conserved syntenic relationships within each of the eight FA desaturase groups. B. napus contains up to 93 FA desaturase genes from the eight groups. Recurrent duplication events in Brassicaceae contributed to the expansion of FA desaturase genes in B. napus, leading to further functional diversification. These FA desaturase genes exhibited spatio-temporal specific expression patterns in different tissues of B. napus, and a set of FA desaturase genes seem to be orchestrated by key transcriptional factors during seed development, such as zf-HD, B3, GATA3, PEI1, NFYA7, YAB1 and YAB2. Altogether, our data have inferred the evolutionary trajectory of this important gene family across distinct plant lineages, providing theoretical basis for future manipulation of FA desaturase genes to improve the seed oil quality of B. napus.

FASN promotes lymph node metastasis in cervical cancer via cholesterol reprogramming and lymphangiogenesis

Cervical cancer (CC) patients with lymph node metastasis (LNM) have a poor prognosis. Clarification of the detailed mechanisms underlying LNM may provide potential clinical therapeutic targets for CC patients with LNM. However, the molecular mechanism of LNM in CC is unclear. In the present study, we demonstrated that fatty acid synthase (FASN), one of the key enzymes in lipid metabolism, had upregulated expression in the CC samples and was correlated with LNM. Moreover, multivariate Cox proportional hazards analysis identified FASN as an independent prognostic factor of CC patients. Furthermore, gain-of-function and loss-of-function approaches showed that FASN promoted CC cell migration, invasion, and lymphangiogenesis. Mechanistically, on the one hand, FASN could regulate cholesterol reprogramming and then activate the lipid raft-related c-Src/AKT/FAK signaling pathway, leading to enhanced cell migration and invasion. On the other hand, FASN induced lymphangiogenesis by secreting PDGF-AA/IGFBP3. More importantly, knockdown of FASN with FASN shRNA or the inhibitors C75 and Cerulenin dramatically diminished LNM in vivo, suggesting that FASN plays an essential role in LNM of CC and the clinical application potential of FASN inhibitors. Taken together, our findings uncover a novel molecular mechanism in LNM of CC and identify FASN as a novel prognostic factor and potential therapeutic target for LNM in CC.

SOAT1 enhances lung cancer invasiveness by stimulating AKT-mediated mitochondrial fragmentation.

Sterol O-acyltransferase 1 (SOAT1) is a key enzyme in lipid metabolism, which mediates cholesterol esterification metabolism and is closely associated with many cancers. However, the role of SOAT1 in lung cancer invasion remains unclear. We found that SOAT1 expression was positively correlated with lung cancer invasion. Downregulation of SOAT1 inhibited invasion, mitochondrial fragmentation, AKT phosphorylation, and phospho-Drp (Ser616) in lung cancer cells and promoted intracellular free cholesterol accumulation. Mechanistically, the AKT phosphorylation inhibitor MK-2206 alleviated both SOAT1 overexpression and high expression-induced mitochondrial fragmentation and lung cancer cell invasion. Furthermore, intracellular free cholesterol accumulation reduced AKT phosphorylation, SREBP1 mRNA expression, cell invasion, and mitochondrial fragmentation in lung cancer cells with high SOAT1 expression. In summary, our findings suggest that SOAT1 promotes lung cancer invasion by activating the PI3K/AKT signaling pathway by downregulating intracellular free cholesterol levels, thereby affecting the regulation of mitochondrial fragmentation.

Seasonal Consumption of Cherries from Different Origins Affects Metabolic Markers and Gene Expression of Lipogenic Enzymes in Rat Liver: A Preliminary Study.

The phytochemical composition of fruits, especially polyphenols, depends on the environmental conditions under which these fruits are cultivated and the agronomic practices followed. Therefore, the consumption of fruits from different origins, with different polyphenol signatures, could have differential effects on health. In addition, recent studies have shown that variation in the biological rhythms due to changes in the photoperiod in the different seasons differentially affect the metabolism in animal models, thus conditioning their response to food consumption. Considering all, this article evaluates the effects of consumption of sweet cherry from different sources, local (LC) and non-local (nLC), on plasma metabolic parameters and the gene expression of key enzymes of lipid metabolism in Fischer 344 rats under photoperiods simulating different seasons. Animals were classified into three photoperiods (L6, L12 and L18) and three treatments (LC, nLC and VH). Both the photoperiod and the treatments significantly affected the evaluated parameters. An effect of the photoperiod on triacylglycerides, non-esterified fatty acids and the mRNA concentration of crucial enzymes from the hepatic lipid metabolism was observed. Furthermore, the consumption of fruit in L12 lowered blood glucose, while the different treatments affected the hepatic expression of genes related with lipidic enzymes.

Genetic association of LPL rs326 with BMI among the Kuwaiti population.

Lipoprotein lipase is a key enzyme in lipid metabolism with reported variants associated with obesity, hypertension, type 2 diabetes, and coronary heart disease. This study was performed to investigate the association between common lipoprotein lipase single nucleotide polymorphisms and metabolic disorders in a sample of Kuwaiti cohort (n = 494). Five lipoprotein lipase variants (rs1801177, rs295, rs326, ss2137497749, and ss2137497750) across the lipoprotein lipase gene were genotyped by real-time PCR employing the TaqMan allele discrimination assay. Genotype, allelic frequencies, and Hardy-Weinberg Equilibrium were determined for each variant in the cohort followed by multivariate and logistic regression analysis. A novel finding was observed for the G allele of single nucleotide polymorphism rs326 which was associated with increased BMI after adjusting for age and sex (β = 1.04; 95% confidence interval = 0.15-1.94; P = 0.02). Moreover, a significant difference in the distribution of the minor C allele of rs295 among coronary heart disease subjects compared with noncoronary heart disease, however, this significance was diminished after controlling for age, sex, and BMI. This study demonstrated that lipoprotein lipase rs326 may be indicative for the increased risk of obesity and possibly rs295 for coronary heart disease. The findings are also in agreement with other reports suggesting that intronic variants are important genetic markers in association studies. The findings warrant further studies in a large cohort to confirm and validate the results presented.

Aberrant lipid metabolism reprogramming and immune microenvironment for gastric cancer: a literature review.

ObjectiveWe summarize the aberrant lipid metabolism disorders associated with enzyme activity and expression changes and related immune microenvironment for gastric cancer.BackgroundGastric cancer is a malignant tumor of the primary digestive system with high incidence, poor prognosis characterized by extensive metastasis and poor effect with radiotherapy and chemotherapy. One of the most important metabolic characteristics of cancer cells is lipid metabolism reprogramming to adapt to the tumor micro-environment.MethodsThe focus of research in recent years has also been on lipid metabolism disorders, particularly aberrant metabolism of fatty acids (FAs) in gastric cancer cells, as well as an upregulation of the expression and activity of key enzymes in lipid metabolism. These changes remind us of the occurrence and development of gastric cancer. These metabolic changes are not unique to cancer cells. Changes in metabolic procedures also determine the function and viability of immune cells. In the immune microenvironment of gastric cancer, the metabolic competition and interaction between cancer cells and immune cells are not very clear, while a deeper understanding of the topic is critical to targeting the differential metabolic requirements of them that comprise an immune response to cancer offers an opportunity to selectively regulate immune cell function.ConclusionsRecent research suggests that targeting metabolism is an emerging and potentially promising treatment strategy for gastric cancer patients. We need to explore it further.