Ficolin 3 promotes ferroptosis in HCC by downregulating IR/SREBP axis-mediated MUFA synthesis.

BACKGROUND: Targeting ferroptosis has been identified as a promising approach for the development of cancer therapies. Monounsaturated fatty acid (MUFA) is a type of lipid that plays a crucial role in inhibiting ferroptosis. Ficolin 3 (FCN3) is a component of the complement system, serving as a recognition molecule against pathogens in the lectin pathway. Recent studies have reported that FCN3 demonstrates inhibitory effects on the progression of certain tumors. However, whether FCN3 can modulate lipid metabolism and ferroptosis remains largely unknown. METHODS: Cell viability, BODIPY-C11 staining, and MDA assay were carried out to detect ferroptosis. Primary hepatocellular carcinoma (HCC) and xenograft models were utilized to investigate the effect of FCN3 on the development of HCC in vivo. A metabonomic analysis was conducted to assess alterations in intracellular and HCC intrahepatic lipid levels. RESULTS: Our study elucidates a substantial decrease in the expression of FCN3, a component of the complement system, leads to MUFA accumulation in human HCC specimens and thereby significantly promotes ferroptosis resistance. Overexpression of FCN3 efficiently sensitizes HCC cells to ferroptosis, resulting in the inhibition of the oncogenesis and progression of both primary HCC and subcutaneous HCC xenograft. Mechanistically, FCN3 directly binds to the insulin receptor ß (IR-ß) and its pro-form (pro-IR), inhibiting pro-IR cleavage and IR-ß phosphorylation, ultimately resulting in IR-ß inactivation. This inactivation of IR-ß suppresses the expression of sterol regulatory element binding protein-1c (SREBP1c), which subsequently suppresses the transcription of genes related to de novo lipogenesis (DNL) and lipid desaturation, and consequently downregulates intracellular MUFA levels. CONCLUSIONS: These findings uncover a novel regulatory mechanism by which FCN3 enhances the sensitivity of HCC cells to ferroptosis, indicating that targeting FCN3-induced ferroptosis is a promising strategy for HCC treatment.

Bioaccumulation, trophic transfer and risk assessment of polycyclic musk in marine food webs of the Bohai Sea.

Galaxolide (HHCB) and tonalide (AHTN) are dominant musks added to personal care products. However, the accumulate and trophic transfer of SMs through the marine food chain are unclear. In this study, organisms were collected from three bays in Bohai Sea to investigate the bioaccumulation, trophic transfer, and health risk of SMs. The HHCB and AHTN concentrations in the muscles range from 2.75 to 365.40 µg/g lw and 1.04-4.94 µg/g lw, respectively. The median HHCB concentrations in muscles were the highest in Bohai Bay, followed by Laizhou Bay and Liaodong Bay, consistent with the HHCB concentrations in sediments. The different fish tissues from Bohai Bay were analyzed, and the HHCB and AHTN concentrations followed the heart > liver > gill > muscles. The trophic magnification factors (TMF) were lower than 1 and the health risk assessment showed no adverse health effects. The results provide insights into the bioaccumulation and trophic transfer behavior of SMs in marine environments.

Scd1 and monounsaturated lipids are required for autophagy and survival of adipocytes.

OBJECTIVE: Exposure of adipocytes to 'cool' temperatures often found in the periphery of the body induces expression of Stearoyl-CoA Desaturase-1 (Scd1), an enzyme that converts saturated fatty acids to monounsaturated fatty acids. The goal of this study is to further investigate the roles of Scd in adipocytes. METHOD: In this study, we employed Scd1 knockout cells and mouse models, along with pharmacological Scd1 inhibition to dissect the enzyme's function in adipocyte physiology. RESULTS: Our study reveals that production of monounsaturated lipids by Scd1 is necessary for fusion of autophagosomes to lysosomes and that with a Scd1-deficiency, autophagosomes accumulate. In addition, Scd1-deficiency impairs lysosomal and autolysosomal acidification resulting in vacuole accumulation and eventual cell death. Blocking autophagosome formation or supplementation with monounsaturated fatty acids maintains vitality of Scd1-deficient adipocytes. CONCLUSION: This study demonstrates the indispensable role of Scd1 in adipocyte survival, with its inhibition in vivo triggering autophagy-dependent cell death and its depletion in vivo leading to the loss of bone marrow adipocytes.

Biosynthesis of 10-Hydroxy-2-decenoic Acid through a One-Step Whole-Cell Catalysis.

10-Hydroxy-2-decenoic acid (10-HDA) is an important component of royal jelly, known for its antimicrobial, anti-inflammatory, blood pressure-lowering, and antiradiation effects. Currently, 10-HDA biosynthesis is limited by the substrate selectivity of acyl-coenzyme A dehydrogenase, which restricts the technique to a two-step process. This study aimed to develop an efficient and simplified method for synthesizing 10-HDA. In this study, ACOX from Candida tropicalis 1798, which catalyzes 10-hydroxydecanoyl coenzyme A desaturation for 10-HDA synthesis, was isolated and heterologously coexpressed with FadE, Macs, YdiI, and CYP in Escherichia coli/SK after knocking out FadB, FadJ, and FadR genes. The engineered E. coli/AKS strain achieved a 49.8% conversion of decanoic acid to 10-HDA. CYP expression was improved through ultraviolet mutagenesis and high-throughput screening, increased substrate conversion to 75.6%, and the synthesis of 10-HDA was increased to 0.628 g/L in 10 h. This is the highest conversion rate and product concentration achieved in the shortest time to date. This study provides a simple and efficient method for 10-HDA biosynthesis and offers an effective method for developing strains with high product yields.

SCD1 sustains brown fat sympathetic innervation and thermogenesis during the long-term cold exposure.

Brown fat adipose tissue (BAT) is a therapeutic potential target to improve obesity, diabetes and cold acclimation in mammals. During the long-term cold exposure, the hyperplastic sympathetic network is crucial for BAT the maintain the highly thermogenic status. It has been proved that the sympathetic nervous drives the thermogenic activity of BAT via the release of norepinephrine. However, it is still unclear that how the thermogenic BAT affects the remodeling of the hyperplastic sympathetic network, especially during the long-term cold exposure. Here, we showed that following long-term cold exposure, SCD1-mediated monounsaturated fatty acid biosynthesis pathway was enriched, and the ratios of monounsaturated/saturated fatty acids were significantly up-regulated in BAT. And SCD1-deficiency in BAT decreased the capacity of cold acclimation, and suppressed long-term cold mediated BAT thermogenic activation. Furthermore, by using thermoneutral exposure and sympathetic nerve excision models, we disclosed that SCD1-deficiency in BAT affected the thermogenic activity, depended on sympathetic nerve. In mechanism, SCD1-deficiency resulted in the unbalanced ratio of palmitic acid (PA)/palmitoleic acid (PO), with obviously higher level of PA and lower level of PO. And PO supplement efficiently reversed the inhibitory role of SCD1-deficiency on BAT thermogenesis and the hyperplastic sympathetic network. Thus, our data provided insight into the role of SCD1-mediated monounsaturated fatty acids metabolism to the interaction between thermogenic activity BAT and hyperplastic sympathetic networks, and illustrated the critical role of monounsaturated fatty acids biosynthetic pathway in cold acclimation during the long-term cold exposure.

CD36 maintains lipid homeostasis via selective uptake of monounsaturated fatty acids during matrix detachment and tumor progression.

A high-fat diet (HFD) promotes metastasis through increased uptake of saturated fatty acids (SFAs). The fatty acid transporter CD36 has been implicated in this process, but a detailed understanding of CD36 function is lacking. During matrix detachment, endoplasmic reticulum (ER) stress reduces SCD1 protein, resulting in increased lipid saturation. Subsequently, CD36 is induced in a p38- and AMPK-dependent manner to promote preferential uptake of monounsaturated fatty acids (MUFAs), thereby maintaining a balance between SFAs and MUFAs. In attached cells, CD36 palmitoylation is required for MUFA uptake and protection from palmitate-induced lipotoxicity. In breast cancer mouse models, CD36-deficiency induced ER stress while diminishing the pro-metastatic effect of HFD, and only a palmitoylation-proficient CD36 rescued this effect. Finally, AMPK-deficient tumors have reduced CD36 expression and are metastatically impaired, but ectopic CD36 expression restores their metastatic potential. Our results suggest that, rather than facilitating HFD-driven tumorigenesis, CD36 plays a supportive role by preventing SFA-induced lipotoxicity.

Metabolic engineering of oleaginous yeast in the lipogenic phase enhances production of nervonic acid.

Insufficient biosynthesis efficiency during the lipogenic phase can be a major obstacle to engineering oleaginous yeasts to overproduce very long-chain fatty acids (VLCFAs). Taking nervonic acid (NA, C24:1) as an example, we overcame the bottleneck to overproduce NA in an engineered Rhodosporidium toruloides by improving the biosynthesis of VLCFAs during the lipogenic phase. First, evaluating the catalytic preferences of three plant-derived ketoacyl-CoA synthases (KCSs) rationally guided reconstructing an efficient NA biosynthetic pathway in R. toruloides. More importantly, a genome-wide transcriptional analysis endowed clues to strengthen the fatty acid elongation (FAE) module and identify/use lipogenic phase-activated promoter, collectively addressing the stagnation of NA accumulation during the lipogenic phase. The best-designed strain exhibited a high NA content (as the major component in total fatty acid [TFA], 46.3%) and produced a titer of 44.2 g/L in a 5 L bioreactor. The strategy developed here provides an engineering framework to establish the microbial process of producing valuable VLCFAs in oleaginous yeasts.

Comparison of the Effects of Monounsaturated Fatty Acids and Polyunsaturated Fatty Acids on Liver Lipid Disorders in Obese Mice.

Obesity is a recognized epidemic worldwide, and the accumulation of excess free saturated fatty acids (SFAs) in cells induces cellular lipotoxic damage and increases the risk of a wide spectrum of metabolic diseases including type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD). Monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs) have been reported to combat SFA-induced cellular damage. However, the comparative studies of the two types of unsaturated fatty acids (UFAs) are still limited. We investigated the effects of different MUFAs and PUFAs in the human hepatocyte line L-02 cells in vitro, and in high-fat-diet (HFD)-induced obese C57BL/6 mice in vivo. The results of the in vitro study showed that SFAs induced significant cellular lipotoxic damage, but the combination of MUFAs/PUFAs with SFAs significantly improved the impaired cell viability. Particularly, oleic acid (OA) was superior to eicosapentaenoic acid (EPA), Docosahexaenoic acid (DHA), and arachidonic acid (AA) in terms of its anti-apoptotic effect and inhibition of endoplasmic reticulum (ER) stress. In vivo, both olive-oil-enriched (HFD + OO) and fish-oil-enriched high-fat diets (HFD + FO) reduced hepatic steatosis and improved insulin sensitivity in obese mice. However, FO induced an abnormal increase in serum aspartate aminotransferase (AST) and an increase in the oxidative stress indicator Malondialdehyde (MDA). Liver-targeted lipidomic analysis showed that liver lipid metabolites under the two types of UFA dietary interventions differed from the HFD group, modulating the abundance of some lipid metabolites such as triglycerides (TGs) and glycerophospholipids. Furthermore, the FO diet significantly increased the abundance of the associated FA 20:5 long-chain lipid metabolites, whereas the OO diet regulated the unsaturation of all fatty acids in general and increased the abundance of FA 18:1 in the overall lipid metabolites, especially TGs, which may primarily contribute to the FO, and OO drove protection in NAFLD.

Targeting Fatty Acid Reprogramming Suppresses CARM1-expressing Ovarian Cancer.

The arginine methyltransferase CARM1 exhibits high expression levels in several human cancers, with the trend also observed in ovarian cancer. However, therapeutic approaches targeting tumors that overexpress CARM1 have not been explored. Cancer cells exploit metabolic reprogramming such as fatty acids for their survival. Here we report that CARM1 promotes monounsaturated fatty acid synthesis and fatty acid reprogramming represents a metabolic vulnerability for CARM1-expressing ovarian cancer. CARM1 promotes the expression of genes encoding rate-limiting enzymes of de novo fatty acid metabolism such as acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FASN). In addition, CARM1 upregulates stearoyl-CoA desaturase 1 (SCD1) that produces monounsaturated fatty acid by desaturation. Thus, CARM1 enhances de novo fatty acids synthesis which was subsequently utilized for synthesis of monounsaturated fatty acids. Consequently, inhibition of SCD1 suppresses the growth of ovarian cancer cells in a CARM1 status-dependent manner, which was rescued by the addition of monounsaturated fatty acids. Consistently, CARM1-expressing cells were more tolerant to the addition of saturated fatty acids. Indeed, SCD1 inhibition demonstrated efficacy against ovarian cancer in both orthotopic xenograft and syngeneic mouse models in a CARM1-dependent manner. In summary, our data show that CARM1 reprograms fatty acid metabolism and targeting SCD1 through pharmacological inhibition can serve as a potent therapeutic approach for CARM1-expressing ovarian cancers. Significance: CARM1 reprograms fatty acid metabolism transcriptionally to support ovarian cancer growth by producing monounsaturated fatty acids, supporting SCD1 inhibition as a rational strategy for treating CARM1-expressing ovarian cancer.

Unveiling the MUFA-Cancer Connection: Insights from Endogenous and Exogenous Perspectives.

Monounsaturated fatty acids (MUFAs) have been the subject of extensive research in the field of cancer due to their potential role in its prevention and treatment. MUFAs can be consumed through the diet or endogenously biosynthesized. Stearoyl-CoA desaturases (SCDs) are key enzymes involved in the endogenous synthesis of MUFAs, and their expression and activity have been found to be increased in various types of cancer. In addition, diets rich in MUFAs have been associated with cancer risk in epidemiological studies for certain types of carcinomas. This review provides an overview of the state-of-the-art literature on the associations between MUFA metabolism and cancer development and progression from human, animal, and cellular studies. We discuss the impact of MUFAs on cancer development, including their effects on cancer cell growth, migration, survival, and cell signaling pathways, to provide new insights on the role of MUFAs in cancer biology.

Stearoyl-CoA Desaturase 1 as a Therapeutic Biomarker: Focusing on Cancer Stem Cells.

The dysregulation of lipid metabolism and alterations in the ratio of monounsaturated fatty acids (MUFAs) to saturated fatty acids (SFAs) have been implicated in cancer progression and stemness. Stearoyl-CoA desaturase 1 (SCD1), an enzyme involved in lipid desaturation, is crucial in regulating this ratio and has been identified as an important regulator of cancer cell survival and progression. SCD1 converts SFAs into MUFAs and is important for maintaining membrane fluidity, cellular signaling, and gene expression. Many malignancies, including cancer stem cells, have been reported to exhibit high expression of SCD1. Therefore, targeting SCD1 may provide a novel therapeutic strategy for cancer treatment. In addition, the involvement of SCD1 in cancer stem cells has been observed in various types of cancer. Some natural products have the potential to inhibit SCD1 expression/activity, thereby suppressing cancer cell survival and self-renewal activity.

Nobiletin Ameliorates Nonalcoholic Fatty Liver Disease by Regulating Gut Microbiota and Myristoleic Acid Metabolism.

Disturbance of the gut microbiota plays a critical role in the development of nonalcoholic fatty liver disease (NAFLD). Increasing evidence supports that natural products may serve as prebiotics to regulate the gut microbiota in the treatment of NAFLD. In the present study, the effect of nobiletin, a naturally occurring polymethoxyflavone, on NAFLD was evaluated, and metabolomics, 16S rRNA gene sequencing, and transcriptomics analysis were performed to determine the underlying mechanism of nobiletin, and the key bacteria and metabolites screened were confirmed by in vivo experiment. Nobiletin treatment could significantly reduce lipid accumulation in high-fat/high-sucrose diet-fed mice. 16S rRNA analysis demonstrated that nobiletin could reverse the dysbiosis of gut microbiota in NAFLD mice and nobiletin could regulate myristoleic acid metabolism, as revealed by untargeted metabolomics analysis. Treatment with the bacteria Allobaculum stercoricanis, Lactobacillus casei, or the metabolite myristoleic acid displayed a protective effect on liver lipid accumulation under metabolic stress. These results indicated that nobiletin might target gut microbiota and myristoleic acid metabolism to ameliorate NAFLD.

Overproduction of palmitoleic acid from corn stover hydrolysate by engineered Saccharomyces cerevisiae.

Palmitoleic acid (POA) has been widely applied to nutrition and pharmaceutical industry. However, high cost of scale-up fermentation restricts the extensive application of POA. Hence, we investigated the availability of corn stover hydrolysate (CSH) as carbon source in POA production by engineered S. cerevisiae. Although the yeast growth was inhibited to some extent by CSH, the POA production with CSH was slightly higher than that with pure glucose. The C/N ratio of 120 and addition of 1 g/L lysine raised the POA titer up to 2.19 g/L and 2.05 g/L, respectively. Two-stage cultivation could increase the POA titer by upregulating the gene expression of key enzymes in fatty acid synthesis pathway. A high POA content of 57.5% (v/v) and a highest POA titer of 6.56 g/L were achieved under the optimized conditions. These findings provide a feasible approach for sustainable production of POA or its derivatives from CSH.

Combining orthogonal plant and non-plant fatty acid biosynthesis pathways for efficient production of microbial oil enriched in nervonic acid in Yarrowia lipolytica.

Nervonic acid has proven efficacy in brain development and the prevention of neurodegenerative diseases. Here, an alternative and sustainable strategy for nervonic acid-enriched plant oil production was established. Different ß-ketoacyl-CoA synthases and heterologous Δ15 desaturase were co-expressed, combined with the deletion of the ß-oxidation pathway to construct orthogonal plant and non-plant nervonic acid biosynthesis pathways in Yarrowia lipolytica. A "block-pull-restrain" strategy was further applied to improve the supply of stearic acid as the precursor of the non-plant pathway. Then, lysophosphatidic acid acyltransferase from Malania oleifera (MoLpaat) was identified, which showed specificity for nervonic acid. Endogenous LPAAT was exchanged by MoLPAAT resulted in 17.10 % nervonic acid accumulation. Finally, lipid metabolism was engineered and cofactor supply was increased to boost the lipid accumulation in a stable null-hyphal strain. The final strain produced 57.84 g/L oils with 23.44 % nervonic acid in fed-batch fermentation, which has the potential to substitute nervonic acid-enriched plant oil.

Quorum-Sensing Signaling Molecule 2-Aminoacetophenone Mediates the Persistence of Pseudomonas aeruginosa in Macrophages by Interference with Autophagy through Epigenetic Regulation of Lipid Biosynthesis.

Macrophages are crucial components of the host's defense against pathogens. Recent studies indicate that macrophage functions are influenced by lipid metabolism. However, knowledge of how bacterial pathogens exploit macrophage lipid metabolism for their benefit remains rudimentary. We have shown that the Pseudomonas aeruginosa MvfR-regulated quorum-sensing (QS) signaling molecule 2-aminoacetophenone (2-AA) mediates epigenetic and metabolic changes associated with this pathogen's persistence in vivo. We provide evidence that 2-AA counteracts the ability of macrophages to clear the intracellular P. aeruginosa, leading to persistence. The intracellular action of 2-AA in macrophages is linked to reduced autophagic functions and the impaired expression of a central lipogenic gene, stearoyl-CoA desaturase 1 (Scd1), which catalyzes the biosynthesis of monounsaturated fatty acids. 2-AA also reduces the expression of the autophagic genes Unc-51-like autophagy activating kinase 1 (ULK1) and Beclin1 and the levels of the autophagosomal membrane protein microtubule-associated protein 1, light chain 3 isoform B (LC3B) and p62. Reduced autophagy is accompanied by the reduced expression of the lipogenic gene Scd1, preventing bacterial clearance. Adding the SCD1 substrates palmitoyl-CoA and stearoyl-CoA increases P. aeruginosa clearance by macrophages. The impact of 2-AA on lipogenic gene expression and autophagic machinery is histone deacetylase 1 (HDAC1) mediated, implicating the HDAC1 epigenetic marks at the promoter sites of Scd1 and Beclin1 genes. This work provides novel insights into the complex metabolic alterations and epigenetic regulation promoted by QS and uncovers additional 2-AA actions supporting P. aeruginosa sustainment in macrophages. These findings may aid in designing host-directed therapeutics and protective interventions against P. aeruginosa persistence. IMPORTANCE This work sheds new light on how P. aeruginosa limits bacterial clearance in macrophages through 2-aminoacetophenone (2-AA), a secreted signaling molecule by this pathogen that is regulated by the quorum-sensing transcription factor MvfR. The action of 2-AA on the lipid biosynthesis gene Scd1 and the autophagic genes ULK1 and Beclin1 appears to secure the reduced intracellular clearance of P. aeruginosa by macrophages. In support of the 2-AA effect on lipid biosynthesis, the ability of macrophages to reduce the intracellular P. aeruginosa burden is reinstated following the supplementation of palmitoyl-CoA and stearoyl-CoA. The 2-AA-mediated reduction of Scd1 and Beclin1 expression is linked to chromatin modifications, implicating the enzyme histone deacetylase 1 (HDAC1), thus opening new avenues for future strategies against this pathogen's persistence. Overall, the knowledge obtained from this work provides for developing new therapeutics against P. aeruginosa.

Role of Stearoyl-CoA Desaturase 1 in Cardiovascular Physiology.

Stearoyl-CoA desaturase is a rate-limiting enzyme in the synthesis of monounsaturated fatty acids. Monounsaturated fatty acids limit the toxicity of exogenous saturated fats. Studies have shown that stearoyl-CoA desaturase 1 is involved in the remodeling of cardiac metabolism. The loss of stearoyl-CoA desaturase 1 reduces fatty acid oxidation and increases glucose oxidation in the heart. Such a change is protective under conditions of a high-fat diet, which reduces reactive oxygen species-generating ß-oxidation. In contrast, stearoyl-CoA desaturase 1 deficiency predisposes individuals to atherosclerosis under conditions of hyperlipidemia but protects against apnea-induced atherosclerosis. Stearoyl-CoA desaturase 1 deficiency also impairs angiogenesis after myocardial infarction. Clinical data show a positive correlation between blood stearoyl-CoA Δ-9 desaturation rates and cardiovascular disease and mortality. Moreover, stearoyl-CoA desaturase inhibition is considered an attractive intervention in some obesity-associated pathologies, and the importance of stearoyl-CoA desaturase in the cardiovascular system might be a limitation for developing such therapy. This review discusses the role of stearoyl-CoA desaturase 1 in the regulation of cardiovascular homeostasis and the development of heart disease and presents markers of systemic stearoyl-CoA desaturase activity and their predictive potential in the diagnosis of cardiovascular disorders.

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.

Saturated fatty acid- and/or monounsaturated fatty acid-containing phosphatidic acids selectively interact with heat shock protein 27.

Diacylglycerol kinase (DGK) α, which is a key enzyme in the progression of cancer and, in contrast, in T-cell activity attenuation, preferentially produces saturated fatty acid (SFA)- and/or monounsaturated fatty acid (MUFA)-containing phosphatidic acids (PAs), such as 16:0/16:0-, 16:0/18:0-, and 16:1/16:1-PA, in melanoma cells. In the present study, we searched for the target proteins of 16:0/16:0-PA in melanoma cells and identified heat shock protein (HSP) 27, which acts as a molecular chaperone and contributes to cancer progression. HSP27 more strongly interacted with PA than other phospholipids, including phosphatidylcholine, phosphatidylserine, phosphatidylglycerol, cardiolipin, phosphatidylinositol, phosphatidylinositol 4-monophosphate, and phosphatidylinositol 4,5-bisphosphate. Moreover, HSP27 is more preferentially bound to SFA- and/or MUFA-containing PAs, including 16:0/16:0- and 16:0/18:1-PAs, than PUFA-containing PAs, including 18:0/20:4- and 18:0/22:6-PA. Furthermore, HSP27 and constitutively active DGKα expressed in COS-7 cells colocalized in a DGK activity-dependent manner. Notably, 16:0/16:0-PA, but not phosphatidylcholine or 16:0/16:0-phosphatidylserine, induced oligomer dissociation of HSP27, which enhances its chaperone activity. Intriguingly, HSP27 protein was barely detectable in Jurkat T cells, while the protein band was intensely detected in AKI melanoma cells. Taken together, these results strongly suggest that SFA- and/or MUFA-containing PAs produced by DGKα selectively target HSP27 and regulate its cancer-progressive function in melanoma cells but not in T cells.

Monounsaturated fatty acid-enriched olive oil exacerbates chronic alcohol-induced hepatic steatosis and liver injury in C57BL/6J mice.

Dietary oil composition determines the pathological processes of alcoholic fatty liver disease (AFLD). Oil rich in saturated fatty acids protects, whereas oil rich in polyunsaturated fatty acids aggravates the alcohol-induced liver injury. However, limited studies have been conducted to address how monounsaturated fatty acids (MUFAs) enriched oil controls the pathological development of AFLD. Therefore, this study was designed to evaluate the effect of MUFA-enriched extra virgin olive oil (OO) on AFLD. Twenty C57BL/6J mice were randomly allocated into four groups and fed modified Lieber-DeCarli liquid diets containing isocaloric maltose dextrin a non-alcohol or alcohol with corn oil and OO for four weeks. Dietary OO significantly exacerbated alcohol-induced liver dysfunction, evidenced by histological examinations and disturbed biochemical parameters. Dietary OO with alcohol decreased hormone-sensitive lipase (HSL), phosphorylated 5'-AMP-activated protein kinase (p-AMPK), and carnitine palmitoyltransferase-Iα (CPT1α) expression, and increased sterol regulatory element-binding protein-1c (SREBP-1c), diacylglycerol acyltransferase-2 (DGAT2), and very low-density lipoprotein receptor (VLDLR) expression in the liver. It also promoted the expression of hepatic interleukin-6 (IL-6) and hepatic tumour necrosis factor-alpha (TNF-α) at the transcriptional level. Additionally, adipose tissue lipolysis partially had an etiologic effect on alcohol-induced hepatic steatosis under OO pretreatment. In conclusion, MUFA-enriched OO exacerbated liver dysfunction in vivo. OO should be cautiously considered as a unique dietary oil source for individuals with AFLD.

The effect of acute and chronic exercise on hepatic lipid composition.

Exercise is recommended for those with, or at risk of nonalcoholic fatty liver disease (NAFLD), owing to beneficial effects on hepatic steatosis and cardiometabolic risk. Whilst exercise training reduces total intrahepatic lipid in people with NAFLD, accumulating evidence indicates that exercise may also modulate hepatic lipid composition. This metabolic influence is important as the profile of saturated (SFA), monounsaturated (MUFA), and polyunsaturated fatty acids (PUFA) dramatically affect the metabolic consequences of hepatic lipid accumulation; with SFA being especially lipotoxic. Relatedly, obesity and NAFLD are associated with hepatic PUFA depletion and elevated SFA. This review summarizes the acute (single bout) and chronic (exercise training) effects of exercise on hepatic lipid composition in rodents (acute studies: n = 3, chronic studies: n = 13) and humans (acute studies: n = 1, chronic studies: n = 3). An increased proportion of hepatic PUFA after acute and chronic exercise is the most consistent finding of this review. Mechanistically, this may relate to an enhanced uptake of adipose-derived PUFA (reflecting habitual diet), particularly in rodents. A relative decrease in the proportion of hepatic MUFA after chronic exercise is also documented repeatedly, particularly in rodent models with elevated hepatic MUFA. This outcome is related to decreased hepatic stearoyl-CoA desaturase-1 activity in some studies. Findings regarding hepatic SFA are less consistent and limited by the absence of metabolic challenge in rodent models. These findings require confirmation in well-controlled interventions in people with NAFLD. These studies will be facilitated by recently validated magnetic resonance spectroscopy techniques, able to precisely quantify hepatic lipid composition in vivo.