Potential Application of the Myocardial Scintigraphy Agent [123I]BMIPP in Colon Cancer Cell Imaging.

[123I]ß-methyl-p-iodophenyl-pentadecanoic acid ([123I]BMIPP), which is used for nuclear medicine imaging of myocardial fatty acid metabolism, accumulates in cancer cells. However, the mechanism of accumulation remains unknown. Therefore, this study aimed to elucidate the accumulation and accumulation mechanism of [123I]BMIPP in cancer cells. We compared the accumulation of [123I]BMIPP in cancer cells with that of [18F]FDG and found that [123I]BMIPP was a much higher accumulation than [18F]FDG. The accumulation of [123I]BMIPP was evaluated in the presence of sulfosuccinimidyl oleate (SSO), a CD36 inhibitor, and lipofermata, a fatty acid transport protein (FATP) inhibitor, under low-temperature conditions and in the presence of etomoxir, a carnitine palmitoyl transferase I (CPT1) inhibitor. The results showed that [123I]BMIPP accumulation was decreased in the presence of SSO and lipofermata in H441, LS180, and DLD-1 cells, suggesting that FATPs and CD36 are involved in [123I]BMIPP uptake in cancer cells. [123I]BMIPP accumulation in all cancer cell lines was significantly decreased at 4 °C compared to that at 37 °C and increased in the presence of etomoxir in all cancer cell lines, suggesting that the accumulation of [123I]BMIPP in cancer cells is metabolically dependent. In a biological distribution study conducted using tumor-bearing mice transplanted with LS180 cells, [123I]BMIPP highly accumulated in not only LS180 cells but also normal tissues and organs (including blood and muscle). The tumor-to-intestine or large intestine ratios of [123I]BMIPP were similar to those of [18F]FDG, and the tumor-to-large-intestine ratios exceeded 1.0 during 30 min after [123I]BMIPP administration in the in vivo study. [123I]BMIPP is taken up by cancer cells via CD36 and FATP and incorporated into mitochondria via CPT1. Therefore, [123I]BMIPP may be useful for imaging cancers with activated fatty acid metabolism, such as colon cancer. However, the development of novel imaging radiotracers based on the chemical structure analog of [123I]BMIPP is needed.

SNPS within the SLC27A6 gene are highly associated with Hu sheep fatty acid content.

Fatty acids (FA) are an important factor affecting meat quality and human health, and the important role of the solute carrier family 27 member 6 (SLC27A6) in FA metabolism has been demonstrated in several species. However, the expression profile of the SLC27A6 in different tissues and the effect of its polymorphism on FA in sheep are currently unknown. This study aimed to explore the differences in FAs in the longissimus dorsi (LD) of 1,085 Hu sheep, the expression profile of SLC27A6, and confirm the effect of single nucleotide polymorphisms (SNPs) on FA phenotypes. We found that many FA phenotypes differ significantly across different seasons, and winter promoted the deposition of polyunsaturated fatty acids (PUFA). The mRNA expression level of SLC27A6 in the lung was significantly higher than that in the heart, testis, and LD. A total of 16 SNPs were detected in the SLC27A6, and 14 SNPs were successfully genotyped by improved multiplex ligase detection reaction (iMLDR) technology. Correlation analysis showed that 7 SNPs significantly affected at least one FA phenotype. Among them, SNP14 contributes to the selection of lamb with low saturated fatty acid content and high PUFA content. Combined genotypes also significantly affected a variety of beneficial FAs such as C18:3n3, C20:4n6, C22:6n3, and monounsaturated fatty acids. This study suggests that SLC27A6 plays an important role in FA metabolism and SNPs that are significantly associated with FA phenotype could be used as potential molecular markers for later targeted regulation of FA profiles in sheep.

Ablation of Fatty Acid Transport Protein-4 Enhances Cone Survival, M-cone Vision, and Synthesis of Cone-Tropic 9-cis-Retinal in rd12 Mouse Model of Leber Congenital Amaurosis.

The canonical visual cycle employing RPE65 as the retinoid isomerase regenerates 11-cis-retinal to support both rod- and cone-mediated vision. Mutations of RPE65 are associated with Leber congenital amaurosis that results in rod and cone photoreceptor degeneration and vision loss of affected patients at an early age. Dark-reared Rpe65-/- mouse has been known to form isorhodopsin that employs 9-cis-retinal as the photosensitive chromophore. The mechanism regulating 9-cis-retinal synthesis and the role of the endogenous 9-cis-retinal in cone survival and function remain largely unknown. In this study, we found that ablation of fatty acid transport protein-4 (FATP4), a negative regulator of 11-cis-retinol synthesis catalyzed by RPE65, increased the formation of 9-cis-retinal, but not 11-cis-retinal, in a light-independent mechanism in both sexes of RPE65-null rd12 mice. Both rd12 and rd12;Fatp4-/- mice contained a massive amount of all-trans-retinyl esters in the eyes, exhibiting comparable scotopic vision and rod degeneration. However, expression levels of M- and S-opsins as well as numbers of M- and S-cones surviving in the superior retinas of rd12;Fatp4-/ - mice were at least twofold greater than those in age-matched rd12 mice. Moreover, FATP4 deficiency significantly shortened photopic b-wave implicit time, improved M-cone visual function, and substantially deaccelerated the progression of cone degeneration in rd12 mice, whereas FATP4 deficiency in mice with wild-type Rpe65 alleles neither induced 9-cis-retinal formation nor influenced cone survival and function. These results identify FATP4 as a new regulator of synthesis of 9-cis-retinal, which is a "cone-tropic" chromophore supporting cone survival and function in the retinas with defective RPE65.

Expression of Placental Lipid Transporters in Pregnancies Complicated by Gestational and Type 1 Diabetes Mellitus.

The objective of the study was to assess the expression of proteins responsible for placental lipid transport in term pregnancies complicated by well-controlled gestational (GDM) and type 1 diabetes mellitus (PGDM). A total of 80 placental samples were obtained from patients diagnosed with PGDM (n = 20), GDM treated with diet (GDMG1, n = 20), GDM treated with diet and insulin (GDMG2, n = 20), and a non-diabetic control group (n = 20). Umbilical and uterine artery blood flows were assessed by means of ultrasound in the period prior to delivery and computer-assisted quantitative morphometry of immunostained placental sections was performed to determine the expression of selected proteins. The morphometric analysis performed for the vascular density-matched placental samples demonstrated a significant increase in the expression of fatty acid translocase (CD36), fatty acid binding proteins (FABP1, FABP4 and FABP5), as well as a decrease in the expression of endothelial lipase (EL) and fatty acid transport protein (FATP4) in the PGDM-complicated pregnancies as compared to the GDMG1 and control groups (p < 0.05). No significant differences with regard to the placental expression of lipoprotein lipase (LPL) and FATP6 protein between GDM/PGDM and non-diabetic patients were noted. Maternal pre-pregnancy weight, body mass index, placental weight as well as the expression of LPL and FABP4 were selected by the linear regression model as the strongest contributors to the fetal birth weight. To conclude, in placentas derived from pregnancies complicated by well-controlled PGDM, the expression of several lipid transporters, including EL, CD36, FATP4, FABP1, FABP4 and FABP5, is altered. Nonetheless, only LPL and FABP4 were significant predictors of the fetal birth weight.

FATP2 regulates osteoclastogenesis by increasing lipid metabolism and ROS production.

Lipid metabolism plays a crucial role in maintaining bone homeostasis, particularly in osteoclasts (OCs) formation. Here, we found that the expression level of FATP2, a transporter for long-chain and very-long-chain fatty acids, was significantly upregulated during OC differentiation and in the bone marrow of mice fed a high-fat diet (HFD). Notably, the use of FATP2 siRNA or a specific inhibitor (Lipofermata) resulted in significant inhibition of OC differentiation, while only slightly affecting osteoblasts. In pathological models of bone loss induced by LPS or ovariectomy, in vivo treatment with Lipofermata was able to rescue the loss of bone mass by inhibiting OC differentiation. RNA sequencing revealed that Lipofermata reduced fatty acid ß-oxidation and inhibited energy metabolism, while regulating ROS metabolism to decrease ROS production, ultimately inhibiting OC differentiation. Treatment with Lipofermata, either in vivo or in vitro, effectively rescued the overactivation of OCs, indicating that FATP2 regulated OC differentiation by modulating fatty acid uptake and energy metabolism. These findings suggested that targeting FATP2 may represent a promising therapeutic approach for pathological osteoporosis.

The inhibition of osteoclastogenesis by Lipofermata, a FATP2 inhibitor, was achieved through the reprogramming of energy metabolism and regulation of ROS levels. In both pathological bone loss and HFD-induced osteoporosis models, the expression levels of FATP2 were significantly upregulated, and Lipofermata demonstrated potential therapeutic effects in the pathological bone loss model.

Degradation of FATTY ACID EXPORT PROTEIN1 by RHOMBOID-LIKE PROTEASE11 contributes to cold tolerance in Arabidopsis.

Plants need to acclimate to different stresses to optimize growth under unfavorable conditions. In Arabidopsis (Arabidopsis thaliana), the abundance of the chloroplast envelope protein FATTY ACID EXPORT PROTEIN1 (FAX1) decreases after the onset of low temperatures. However, how FAX1 degradation occurs and whether altered FAX1 abundance contributes to cold tolerance in plants remains unclear. The rapid cold-induced increase in RHOMBOID-LIKE PROTEASE11 (RBL11) transcript levels, the physical interaction of RBL11 with FAX1, the specific FAX1 degradation after RBL11 expression, and the absence of cold-induced FAX1 degradation in rbl11 loss-of-function mutants suggest that this enzyme is responsible for FAX1 degradation. Proteomic analyses showed that rbl11 mutants have higher levels of FAX1 and other proteins involved in membrane lipid homeostasis, suggesting that RBL11 is a key element in the remodeling of membrane properties during cold conditions. Consequently, in the cold, rbl11 mutants show a shift in lipid biosynthesis toward the eukaryotic pathway, which coincides with impaired cold tolerance. To test whether cold sensitivity is due to increased FAX1 levels, we analyzed FAX1 overexpressors. The rbl11 mutants and FAX1 overexpressor lines show superimposable phenotypic defects upon exposure to cold temperatures. Our re-sults show that the cold-induced degradation of FAX1 by RBL11 is critical for Arabidop-sis to survive cold and freezing periods.

Loss of SLC27A5 Activates Hepatic Stellate Cells and Promotes Liver Fibrosis via Unconjugated Cholic Acid.

Although the dysregulation of bile acid (BA) composition has been associated with fibrosis progression, its precise roles in liver fibrosis is poorly understood. This study demonstrates that solute carrier family 27 member 5 (SLC27A5), an enzyme involved in BAs metabolism, is substantially downregulated in the liver tissues of patients with cirrhosis and fibrosis mouse models. The downregulation of SLC27A5 depends on RUNX family transcription factor 2 (RUNX2), which serves as a transcriptional repressor. The findings reveal that experimental SLC27A5 knockout (Slc27a5-/- ) mice display spontaneous liver fibrosis after 24 months. The loss of SLC27A5 aggravates liver fibrosis induced by carbon tetrachloride (CCI4 ) and thioacetamide (TAA). Mechanistically, SLC27A5 deficiency results in the accumulation of unconjugated BA, particularly cholic acid (CA), in the liver. This accumulation leads to the activation of hepatic stellate cells (HSCs) by upregulated expression of early growth response protein 3 (EGR3). The re-expression of hepatic SLC27A5 by an adeno-associated virus or the reduction of CA levels in the liver using A4250, an apical sodium-dependent bile acid transporter (ASBT) inhibitor, ameliorates liver fibrosis in Slc27a5-/- mice. In conclusion, SLC27A5 deficiency in mice drives hepatic fibrosis through CA-induced activation of HSCs, highlighting its significant implications for liver fibrosis treatment.

Copper metabolism-related risk score identifies hepatocellular carcinoma subtypes and SLC27A5 as a potential regulator of cuproptosis.

AIMS: Dysregulated copper metabolism has been noticed in many types of cancer including hepatocellular carcinoma (HCC); however, a comprehensive understanding about this dysregulation still remains unclear in HCC. METHODS: A set of bioinformatic tools was integrated to analyze the expression and prognostic significance of copper metabolism-related genes. A related risk score, termed as CMscore, was developed via univariate Cox regression, least absolute shrinkage and selection operator (LASSO) Cox regression and multivariate Cox regression. Pathway enrichment analyses and tumor immune cell infiltration were further investigated in CMscore stratified HCC patients. Weighted correlation network analysis (WGCNA) was used to identify potential regulator of cuproptosis. RESULTS: Copper metabolism was dysregulated in HCC. HCC patients in the high-CMscore group showed a significantly lower overall survival (OS) and enriched in most cancer-related pathways. Besides, HCC patients with high CMscore had higher expression of pro-tumor immune infiltrates and immune checkpoints. Moreover, cancer patients with high CMscore from two large cohorts exhibited significantly prolonged survival time after immunotherapy. WGCNA and subsequently correlation analysis revealed that SLC27A5 might be a potential regulator of cuproptosis in HCC. In vitro experiments revealed that SLC27A5 inhibited cell proliferation and migration of HCC cells and could upregulate FDX1, the key regulator of cuproptosis. SIGNIFICANCE: The CMscore is helpful in clustering HCC patients with distinct prognosis, gene mutation signatures, and sensitivity to immunotherapy. SLC27A5 might serve as a potential target in the induction of cuproptosis in HCC.

AI-Based Homology Modelling of Fatty Acid Transport Protein 1 Using AlphaFold: Structural Elucidation and Molecular Dynamics Exploration.

Fatty acid transport protein 1 (FATP1) is an integral transmembrane protein that is involved in facilitating the translocation of long-chain fatty acids (LCFA) across the plasma membrane, thereby orchestrating the importation of LCFA into the cell. FATP1 also functions as an acyl-CoA ligase, catalyzing the ATP-dependent formation of fatty acyl-CoA using LCFA and VLCFA (very-long-chain fatty acids) as substrates. It is expressed in various types of tissues and is involved in the regulation of crucial signalling pathways, thus playing a vital role in numerous physiological and pathological conditions. Structural insight about FATP1 is, thus, extremely important for understanding the mechanism of action of this protein and developing efficient treatments against its anomalous expression and dysregulation, which are often associated with pathological conditions such as breast cancer. As of now, there has been no prior prediction or evaluation of the 3D configuration of the human FATP1 protein, hindering a comprehensive understanding of the distinct functional roles of its individual domains. In our pursuit to unravel the structure of the most commonly expressed isoforms of FATP1, we employed the cutting-edge ALPHAFOLD 2 model for an initial prediction of the entire protein's structure. This prediction was complemented by molecular dynamics simulations, focusing on the most promising model. We predicted the structure of FATP1 in silico and thoroughly refined and validated it using coarse and molecular dynamics in the absence of the complete crystal structure. Their relative dynamics revealed the different properties of the characteristic FATP1.

Deep sequencing of circulating miRNAs and target mRNAs level in deep venous thrombosis patients.

Deep venous thrombosis is one of the most common peripheral vascular diseases that lead to major morbidity and mortality. The authors aimed to identify potential differentially expressed miRNAs and target mRNAs, which were helpful in understanding the potential molecule mechanism of deep venous thrombosis. The plasma samples of patients with deep venous thrombosis were obtained for the RNA sequencing. Differentially expressed miRNAs were identified, followed by miRNA-mRNA target analysis. Enrichment analysis was used to analyze the potential biological function of target mRNAs. GSE19151 and GSE173461 datasets were used for expression validation of mRNAs and miRNAs. 131 target mRNAs of 21 differentially expressed miRNAs were identified. Among which, 8 differentially expressed miRNAs including hsa-miR-150-5p, hsa-miR-326, hsa-miR-144-3p, hsa-miR-199a-5p, hsa-miR-199b-5p, hsa-miR-125a-5p, hsa-let-7e-5p and hsa-miR-381-3p and their target mRNAs (PRKCA, SP1, TP53, SLC27A4, PDE1B, EPHB3, IRS1, HIF1A, MTUS1 and ZNF652) were found associated with deep venous thrombosis for the first time. Interestingly, PDE1B and IRS1 had a potential diagnostic value for patients. Additionally, 3 important signaling pathways including p53, PI3K-Akt and MAPK were identified in the enrichment analysis of target mRNAs (TP53, PRKCA and IRS1). Identified circulating miRNAs and target mRNAs and related signaling pathways may be involved in the process of deep venous thrombosis.

Skeletal muscle proteins involved in fatty acid transport influence fatty acid oxidation rates observed during exercise.

Several proteins are implicated in transmembrane fatty acid transport. The purpose of this study was to quantify the variation in fatty acid oxidation rates during exercise explained by skeletal muscle proteins involved in fatty acid transport. Seventeen endurance-trained males underwent a (i) fasted, incremental cycling test to estimate peak whole-body fatty acid oxidation rate (PFO), (ii) resting vastus lateralis microbiopsy, and (iii) 2 h of fed-state, moderate-intensity cycling to estimate whole-body fatty acid oxidation during fed-state exercise (FO). Bivariate correlations and stepwise linear regression models of PFO and FO during 0-30 min (early FO) and 90-120 min (late FO) of continuous cycling were constructed using muscle data. To assess the causal role of transmembrane fatty acid transport in fatty acid oxidation rates during exercise, we measured fatty acid oxidation during in vivo exercise and ex vivo contractions in wild-type and CD36 knock-out mice. We observed a novel, positive association between vastus lateralis FATP1 and PFO and replicated work reporting a positive association between FABPpm and PFO. The stepwise linear regression model of PFO retained CD36, FATP1, FATP4, and FABPpm, explaining ~87% of the variation. Models of early and late FO explained ~61 and ~65% of the variation, respectively. FATP1 and FATP4 emerged as contributors to models of PFO and FO. Mice lacking CD36 had impaired whole-body and muscle fatty acid oxidation during exercise and muscle contractions, respectively. These data suggest that substantial variation in fatty acid oxidation rates during exercise can be explained by skeletal muscle proteins involved in fatty acid transport.

Myeloid-specific fatty acid transport protein 4 deficiency induces a sex-dimorphic susceptibility for nonalcoholic steatohepatitis in mice fed a high-fat, high-cholesterol diet.

Newborns with FATP4 mutations exhibit ichthyosis prematurity syndrome (IPS), and adult patients show skin hyperkeratosis, allergies, and eosinophilia. We have previously shown that the polarization of macrophages is altered by FATP4 deficiency; however, the role of myeloid FATP4 in the pathogenesis of nonalcoholic steatohepatitis (NASH) is not known. We herein phenotyped myeloid-specific Fatp4-deficient (Fatp4M-/-) mice under chow and high-fat, high-cholesterol (HFHC) diet. Bone-marrow-derived macrophages (BMDMs) from Fatp4M-/- mice showed significant reduction in cellular sphingolipids in males and females, and additionally phospholipids in females. BMDMs and Kupffer cells from Fatp4M-/- mice exhibited increased LPS-dependent activation of proinflammatory cytokines and transcription factors PPARγ, CEBPα, and p-FoxO1. Correspondingly, these mutants under chow diet displayed thrombocytopenia, splenomegaly, and elevated liver enzymes. After HFHC feeding, Fatp4M-/- mice showed increased MCP-1 expression in livers and subcutaneous fat. Plasma MCP-1, IL4, and IL13 levels were elevated in male and female mutants, and female mutants additionally showed elevation of IL5 and IL6. After HFHC feeding, male mutants showed an increase in hepatic steatosis and inflammation, whereas female mutants showed a greater severity in hepatic fibrosis associated with immune cell infiltration. Thus, myeloid-FATP4 deficiency led to steatotic and inflammatory NASH in males and females, respectively. Our work offers some implications for patients with FATP4 mutations and also highlights considerations in the design of sex-targeted therapies for NASH treatment.NEW & NOTEWORTHY FATP4 deficiency in BMDMs and Kupffer cells led to increased proinflammatory response. Fatp4M-/- mice displayed thrombocytopenia, splenomegaly, and elevated liver enzymes. In response to HFHC feeding, male mutants were prone to hepatic steatosis, whereas female mutants showed exaggerated fibrosis. Our study provides insights into a sex-dimorphic susceptibility to NASH by myeloid-FATP4 deficiency.

SLC27A4-mediated selective uptake of mono-unsaturated fatty acids promotes ferroptosis defense in hepatocellular carcinoma.

Aberrant lipid metabolism mediated by the selective transport of fatty acids plays vital roles in cancer initiation, progression, and therapeutic failure. However, the biological function and clinical significance of abnormal fatty acid transporters in human cancer remain unclear. In the present study, we reported that solute carrier family 27 member 4 (SLC27A4) is significantly overexpressed in 21 types of human cancer, especially in the fatty acids-enriched microenvironment surrounding hepatocellular carcinoma (HCC), breast cancer, and ovarian cancer. Upregulated SLC27A4 expression correlated with shorter overall and relapse-free survival of patients with HCC, breast cancer, or ovarian cancer. Lipidomic analysis revealed that overexpression of SLC27A4 significantly promoted the selective uptake of mono-unsaturated fatty acids (MUFAs), which induced a high level of MUFA-containing phosphatidylcholine and phosphatidylethanolamine in HCC cells, consequently resulting in resistance to lipid peroxidation and ferroptosis. Importantly, silencing SLC27A4 significantly promoted the sensitivity of HCC to sorafenib treatment, both in vitro and in vivo. Our findings revealed a plausible role for SLC27A4 in ferroptosis defense via lipid remodeling, which might represent an attractive therapeutic target to increase the effectiveness of sorafenib treatment in HCC.

Differential Expression of FXR and Genes Involved in Inflammation and lipid Metabolism Indicate Adipose Tissue Dysfunction in Gestational Diabetes.

BACKGROUND: Gestational diabetes mellitus (GDM) is the most frequent metabolic alteration in pregnancy. Several abnormalities in visceral adipose tissue (VAT) have been described as part of its pathophysiology including hypertrophy, inflammation and altered lipid metabolism. Farnesoid X receptor (FXR) is involved in adipocyte physiology and inflammation, so its expression may correlate with the expression of tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), lipoprotein lipase (LPL), and two fatty acid transporters (SLC27A2, and SLC27A4). AIM: To compare the FXR, LPL, SLC27A2, SLC27A4, TNF-α, and IL-10 mRNA expression in VAT between women with GDM and healthy pregnant (HP) women. Secondarily, to evaluate the potential correlation between these expression levels. MATERIALS AND METHODS: Cross-sectional study of 50 GDM and 50 HP women. Conventional biochemical tests were performed and relative mRNA expression in VAT was measured by RT-qPCR. RESULTS: Gene expression levels of FXR and IL-10 were lower, whereas those of LPL, as well as the TNF-α/IL-10 ratio, were higher in women with GDM compared to HP. Pre-pregnancy BMI was the main significant independent variable for FXR levels in VAT from women with GDM. In all women, LPL expression levels correlated positively with those of SLC27A2. Only in women with GDM, IL-10 expression levels correlated negatively with those of SLC27A2, and SLC27A4. CONCLUSIONS: GDM is associated with decreased expression of FXR and IL-10 and increased expression of LPL, as well as a higher TNF/IL-10 ratio in VAT. These results suggest increased lipid storage and pro-inflammatory state indicating VAT dysfunction in this metabolic disorder.

Fatty Acyl Coenzyme A Synthetase Fat1p Regulates Vacuolar Structure and Stationary-Phase Lipophagy in Saccharomyces cerevisiae.

During yeast stationary phase, a single spherical vacuole (lysosome) is created by the fusion of several small ones. Moreover, the vacuolar membrane is reconstructed into two distinct microdomains. Little is known, however, about how cells maintain vacuolar shape or regulate their microdomains. Here, we show that Fat1p, a fatty acyl coenzyme A (acyl-CoA) synthetase and fatty acid transporter, and not the synthetases Faa1p and Faa4p, is essential for vacuolar shape preservation, the development of vacuolar microdomains, and cell survival in stationary phase of the yeast Saccharomyces cerevisiae. Furthermore, Fat1p negatively regulates general autophagy in both log- and stationary-phase cells. In contrast, Fat1p promotes lipophagy, as the absence of FAT1 limits the entry of lipid droplets into the vacuole and reduces the degradation of liquid droplet (LD) surface proteins. Notably, supplementing with unsaturated fatty acids or overexpressing the desaturase Ole1p can reverse all aberrant phenotypes caused by FAT1 deficiency. We propose that Fat1p regulates stationary phase vacuolar morphology, microdomain differentiation, general autophagy, and lipophagy by controlling the degree of fatty acid saturation in membrane lipids. IMPORTANCE The ability to sense environmental changes and adjust the levels of cellular metabolism is critical for cell viability. Autophagy is a recycling process that makes the most of already-existing energy resources, and the vacuole/lysosome is the ultimate autophagic processing site in cells. Lipophagy is an autophagic process to select degrading lipid droplets. In yeast cells in stationary phase, vacuoles fuse and remodel their membranes to create a single spherical vacuole with two distinct membrane microdomains, which are required for yeast lipophagy. In this study, we discovered that Fat1p was capable of rapidly responding to changes in nutritional status and preserving cell survival by regulating membrane lipid saturation to maintain proper vacuolar morphology and the level of lipophagy in the yeast S. cerevisiae. Our findings shed light on how cells maintain vacuolar structure and promote the differentiation of vacuole surface microdomains for stationary-phase lipophagy.

Fatty acid transport proteins (FATPs) in cancer.

Lipids play pivotal roles in cancer biology. Lipids have a wide range of biological roles, especially in cell membrane synthesis, serve as energetic molecules in regulating energy-demanding processes; and they play a significant role as signalling molecules and modulators of numerous cellular functions. Lipids may participate in the development of cancer through the fatty acid signalling pathway. Lipids consumed in the diet act as a key source of extracellular pools of fatty acids transported into the cellular system. Increased availability of lipids to cancer cells is due to increased uptake of fatty acids from adipose tissues. Lipids serve as a source of energy for rapidly dividing cancerous cells. Surviving requires the swift synthesis of biomass and membrane matrix to perform exclusive functions such as cell proliferation, growth, invasion, and angiogenesis. FATPs (fatty acid transport proteins) are a group of proteins involved in fatty acid uptake, mainly localized within cells and the cellular membrane, and have a key role in long-chain fatty acid transport. FATPs are composed of six isoforms that are tissue-specific and encoded by a specific gene. Previous studies have reported that FATPs can alter fatty acid metabolism, cell growth, and cell proliferation and are involved in the development of various cancers. They have shown increased expression in most cancers, such as melanoma, breast cancer, prostate cancer, renal cell carcinoma, hepatocellular carcinoma, bladder cancer, and lung cancer. This review introduces a variety of FATP isoforms and summarises their functions and their possible roles in the development of cancer.

Feedback loop between fatty acid transport protein 2 and receptor interacting protein 3 pathways promotes polymorphonuclear neutrophil myeloid-derived suppressor cells-potentiated suppressive immunity in bladder cancer.

BACKGROUND: Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) promote tumor immune tolerance and cause tumor immunotherapy failure. In this study, we found that high PMN-MDSCs infiltration, overexpressed fatty acid transporter protein 2 (FATP2) and underexpressed receptor-interacting protein kinase 3 (RIPK3) existed in the mouse and human bladder cancer tissues. However, the related mechanisms remain largely unknown. METHODS AND RESULTS: Both FATP2 and RIPK3 expressions were associated with clinical stage. FATP2 knockout or up-regulating RIPK3 reduced the synthesis of prostaglandin E2 (PGE2) in PMN-MDSCs, attenuated the suppressive activity of PMN-MDSCs on CD8+ T cells functions and inhibited the tumor growth. There was a PGE2-mediated feedback loop between FATP2 and RIPK3 pathways, which markedly promoted the immunosuppressive activity of PMN-MDSCs. Combination therapy with inhibition of FATP2 and activation of RIPK3 can effectively inhibit tumor growth. CONCLUSIONS: This study demonstrated that a feedback loop between FATP2 and RIPK3 pathways in PMN-MDSCs significantly promoted the synthesis of PGE2, which severely impaired the CD8+ T cell functions. This study may provide new ideas for immunotherapy of human bladder cancer.

Role of fatty acid transport protein 4 in metabolic tissues: insights into obesity and fatty liver disease.

Fatty acid (FA) metabolism is a series of processes that provide structural substances, signalling molecules and energy. Ample evidence has shown that FA uptake is mediated by plasma membrane transporters including FA transport proteins (FATPs), caveolin-1, fatty-acid translocase (FAT)/CD36, and fatty-acid binding proteins. Unlike other FA transporters, the functions of FATPs have been controversial because they contain both motifs of FA transport and fatty acyl-CoA synthetase (ACS). The widely distributed FATP4 is not a direct FA transporter but plays a predominant function as an ACS. FATP4 deficiency causes ichthyosis premature syndrome in mice and humans associated with suppression of polar lipids but an increase in neutral lipids including triglycerides (TGs). Such a shift has been extensively characterized in enterocyte-, hepatocyte-, and adipocyte-specific Fatp4-deficient mice. The mutants under obese and non-obese fatty livers induced by different diets persistently show an increase in blood non-esterified free fatty acids and glycerol indicating the lipolysis of TGs. This review also focuses on FATP4 role on regulatory networks and factors that modulate FATP4 expression in metabolic tissues including intestine, liver, muscle, and adipose tissues. Metabolic disorders especially regarding blood lipids by FATP4 deficiency in different cell types are herein discussed. Our results may be applicable to not only patients with FATP4 mutations but also represent a model of dysregulated lipid homeostasis, thus providing mechanistic insights into obesity and development of fatty liver disease.

Solute Carrier Family 27 Member 6 (SLC27A6) Possibly Promotes the Proliferation of Papillary Thyroid Cancer by Regulating c-MYC.

To investigate the expression and mechanism of LSC27A6 in papillary thyroid cancer (PTC). We analyzed the differential expression of SLC27A6 in PTC tissues and normal tissues based on the TCGA database and validated it using immunohistochemistry. Wilcoxon rank sum, chi-square test, or Fisher exact exam were used to analyze the relationship between the expression of SLC27A6 and clinicopathological information. Samples were divided into two groups according to whether BRAF was mutated or not, and Wilcoxon rank sum was used to determine whether the expression of SLC27A6 was related to BRAF mutation. The effects of SLC27A6 on the proliferation, migration, and apoptosis of PTC cells were detected by cell counting kit-8 (CCK8), colony formation assay, transwell assay, and flow cytometry. Spearman correlation analysis was used to evaluate the relationship between SLC27A6 and c-MYC. Protein expression was detected by Western blot. The expression of SLC27A6 was higher in PTC and positively correlated with N stage. SLC27A6 expression was higher in samples with BRAF mutations. Down-regulation of SLC27A6 inhibited cell proliferation, migration, and invasion and induced apoptosis. Spearman correlation analysis showed that SLC27A6 was positively correlated with c-MYC. Knockdown of SLC27A6 inhibited c-MYC expression. Our results suggest that SLC27A6 is overexpressed in PTC tissues and affects the progression of PTC by regulating c-MYC.

Two AMP-Binding Domain Proteins from Rhizophagus irregularis Involved in Import of Exogenous Fatty Acids.

Arbuscular mycorrhizal fungi (AMF) colonize roots, where they provide nutrients in exchange for sugars and lipids. Because AMF lack genes for cytosolic fatty acid de novo synthase (FAS), they depend on host-derived fatty acids. AMF colonization is accompanied by expression of specific lipid genes and synthesis of sn-2 monoacylglycerols (MAGs). It is unknown how host-derived fatty acids are taken up by AMF. We describe the characterization of two AMP-binding domain protein genes from Rhizophagus irregularis, RiFAT1 and RiFAT2, with sequence similarity to Saccharomyces cerevisiae fatty acid transporter 1 (FAT1). Uptake of 13C-myristic acid (14:0) and, to a lesser extent, 13C-palmitic acid (16:0) was enhanced after expression of RiFAT1 or RiFAT2 in S. cerevisiae Δfat1 cells. The uptake of 2H-labeled fatty acids from 2H-myristoylglycerol or 2H-palmitoylglycerol was also increased after RiFAT1 and RiFAT2 expression in Δfat, but intact 2H-MAGs were not detected. RiFAT1 and RiFAT2 expression was induced in colonized roots compared with extraradical mycelium. 13C-label in the AMF-specific palmitvaccenic acid (16:1Δ11) and eicosatrienoic acid (20:3) were detected in colonized roots only when 13C2-acetate was supplemented but not 13C-fatty acids, demonstrating that de novo synthesized, host-derived fatty acids are rapidly taken up by R. irregularis from the roots. The results show that RiFAT1 and RiFAT2 are involved in the uptake of myristic acid (14:0) and palmitic acid (16:0), while fatty acids from MAGs are only taken up after hydrolysis. Therefore, the two proteins might be involved in fatty acid import into the fungal arbuscules in colonized roots.[Formula: see text] Copyright © 2022 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.