Emerging role of PES1 in disease: A promising therapeutic target?

Pescadillo ribosomal biogenesis factor 1 (PES1), a nucleolar protein initially identified in zebrafish, plays an important role in embryonic development and ribosomal biogenesis. Notably, PES1 has been found to be overexpressed in a number of cancer types, where it contributes to tumorigenesis and cancer progression by promoting cell proliferation, suppressing cellular senescence, modulating the tumor microenvironment (TME) and promoting drug resistance in cancer cells. Moreover, recent emerging evidence suggests that PES1 expression is significantly elevated in the livers of Type 2 diabetes mellitus (T2DM) and obese patients, indicating its involvement in the pathogenesis of metabolic diseases through lipid metabolism regulation. In this review, we present the structural characteristics and biological functions of PES1, as well as complexes in which PES1 participates. Furthermore, we comprehensively summarize the multifaceted role of PES1 in various diseases and the latest insights into its underlying molecular mechanisms. Finally, we discuss the potential clinical translational perspectives of targeting PES1, highlighting its promising as a therapeutic intervention and treatment target.

Identification of Senkyunolide I as a novel modulator of hepatic steatosis and PPARα signaling in zebrafish and hamster models.

ETHNOPHARMACOLOGICAL RELEVANCE: Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver-related morbidity and mortality, with hepatic steatosis being the hallmark symptom. Salvia miltiorrhiza Bunge (Smil, Dan-Shen) and Ligusticum striatum DC (Lstr, Chuan-Xiong) are commonly used to treat cardiovascular diseases and have the potential to regulate lipid metabolism. However, whether Smil/Lstr combo can be used to treat NAFLD and the mechanisms underlying its lipid-regulating properties remain unclear. PURPOSE: To assess the feasibility and reliability of a short-term high-fat diet (HFD) induced zebrafish model for evaluating hepatic steatosis phenotype and to investigate the liver lipid-lowering effects of Smil/Lstr, as well as its active components. METHODS: The phenotypic alterations of liver and multiple other organ systems were examined in the HFD zebrafish model using fluorescence imaging and histochemistry. The liver-specific lipid-lowering effects of Smil/Lstr combo were evaluated endogenously. The active molecules and functional mechanisms were further explored in zebrafish, human hepatocytes, and hamster models. RESULTS: In 5-day HFD zebrafish, significant lipid accumulation was detected in the blood vessels and the liver, as evidenced by increased staining with Oil Red O and fluorescent lipid probes. Hepatic hypertrophy was observed in the model, along with macrovesicular steatosis. Smil/Lstr combo administration effectively restored the lipid profile and alleviated hepatic hypertrophy in the HFD zebrafish. In oleic-acid stimulated hepatocytes, Smil/Lstr combo markedly reduced lipid accumulation and cell damage. Subsequently, based on zebrafish phenotypic screening, the natural phthalide senkyunolide I (SEI) was identified as a major molecule mediating the lipid-lowering activities of Smil/Lstr combo in the liver. Moreover, SEI upregulated the expression of the lipid metabolism regulator PPARα and downregulated fatty acid translocase CD36, while a PPARα antagonist sufficiently blocked the regulatory effect of SEI on hepatic steatosis. Finally, the roles of SEI on hepatic lipid accumulation and PPARα signaling were further verified in the hamster model. CONCLUSIONS: We proposed a zebrafish-based screening strategy for modulators of hepatic steatosis and discovered the regulatory roles of Smil/Lstr combo and its component SEI on liver lipid accumulation and PPARα signaling, suggesting their potential value as novel candidates for NAFLD treatment.

Mechanisms of hepatic and renal injury in lipid metabolism disorders in metabolic syndrome.

Metabolic syndrome (MetS) is a group of metabolic abnormalities that identifies people at risk for diabetes and cardiovascular disease. MetS is characterized by lipid disorders, and non-alcoholic fatty liver disease (NAFLD) and diabetic kidney disease (DKD) are thought to be the common hepatic and renal manifestations of MetS following abnormal lipid metabolism. This paper reviews the molecular mechanisms of lipid deposition in NAFLD and DKD, highlighting the commonalities and differences in lipid metabolic pathways in NAFLD and DKD. Hepatic and renal steatosis is the result of lipid acquisition exceeding lipid processing, i.e., fatty acid uptake and lipid regeneration exceed fatty acid oxidation and export. This process is directly regulated by the interactions of nuclear receptors, transporter proteins and transcription factors, whereas pathways such as oxidative stress, autophagy, cellular pyroptosis and gut flora are also key regulatory hubs for lipid metabolic homeostasis but act slightly differently in the liver and kidney. Such insights based on liver-kidney similarities and differences offer potential options for improved treatment.

Effect and mechanism of GPR75 in metabolic dysfunction-related steatosis liver disease.

Research on G protein-coupled receptor 75 (GPR75) in metabolic dysfunction-related steatosis liver disease (MASLD) reveals its potential role in regulating body weight and energy balance. Loss-of-function mutations in the GPR75 gene are significantly associated with lower body mass index and reduced body weight. Studies demonstrate that GPR75 knockout mice exhibit lower fasting blood glucose levels, improved glucose homeostasis, and significant prevention of high-fat diet-induced MASLD. The absence of GPR75 reduces fat accumulation by beneficially altering energy balance rather than restricting adipose tissue expansion. Moreover, female GPR75 knockout mice show greater protection against lipid accumulation on a high-fat diet compared to males, potentially attributed to higher physical activity and energy expenditure. However, current research primarily relies on mouse models, and its applicability to humans requires further validation. Future studies should explore the role of GPR75 across diverse populations, its clinical potential, and delve into its specific mechanisms and interactions with other metabolic pathways. Ultimately, targeted therapies based on GPR75 could offer novel strategies for the prevention and treatment of MASLD and other metabolic disorders.

The emerging role of ethanolamine phosphate phospholyase in regulating hepatic phosphatidylethanolamine and plasma lipoprotein metabolism in mice.

Ethanolamine phosphate phospholyase (ETNPPL) is an enzyme that irreversibly degrades phospho-ethanolamine (p-ETN), an intermediate in the Kennedy pathway of phosphatidylethanolamine (PE) biosynthesis. PE is the second most abundant phospholipid in mammalian membranes. Disturbance of hepatic phospholipid homeostasis has been linked to the development of metabolic dysfunction-associated steatotic liver disease (MASLD). We generated whole-body Etnppl knockout mice to investigate the impact of genetic deletion of Etnppl on hepatic lipid metabolism. Primary hepatocytes isolated from Etnppl-/- mice showed increased conversion of [3H]ethanolamine to [3H]p-ETN and [3H]PE compared to Etnppl+/+ mice. Male and female Etnppl+/+ and Etnppl-/- mice were fed either a chow or a western-type diet (WTD). Irrespective of diet, Etnppl-/- mice had elevated fasting levels of total plasma cholesterol, triglyceride (TG) and apolipoprotein B100 (VLDL particles). Interestingly, hepatic TG secretion was unchanged between groups. Although hepatic lipids (phosphatidylcholine (PC), PE, TG, and cholesterol) were not different between mice, RNA sequencing analysis showed downregulation in genes related to cholesterol biosynthesis in Etnppl-/- mice. Furthermore, hepatic low-density lipoprotein receptor-related protein1 (LRP1) protein level was lower in female Etnppl-/- mice, which may indicate reduced uptake of remnant VLDL particles from circulation. Hepatic PE levels were only increased in WTD-fed female Etnppl-/- mice, not chow diet-fed mice. However, hepatic lipid accumulation and metabolic dysfunction-associated steatohepatitis (MASH) development were unchanged between Etnppl+/+ and Etnppl-/- mice. To conclude, ETNPPL has a role in regulating plasma lipoprotein metabolism independent of hepatic TG levels.

Adipose stem cells regulate lipid metabolism by upregulating mitochondrial fatty acid ß-oxidation in macrophages to improve the retention rate of transplanted fat.

BACKGROUND: At present, fat transplantation is widely used in the plastic surgery industry, but the long-term preservation rate of transplanted fat decreases because of complications such as oil cysts due to the inability in macrophages to metabolize absorption. In cell-assisted lipotransfer technology, adipose-derived stem cells (ASCs) can influence the inflammatory response of grafts through the immunoregulation in macrophages, and the lipid metabolism in macrophages plays an important role in this process. Therefore, we hypothesized ASCs could improve the retention rate of fat grafts by regulating the progress of lipid metabolism in macrophages. METHODS: We established fat transplantation and ASC-assisted fat transplantation model in C57BL/6 mice in vivo, and bone marrow-derived macrophages cocultured with apoptotic adipocytes were treated with or without ASCs in vitro. Graft retention, tissue structure, fibrosis, macrophage phenotype transformation, lipid deposition, mitochondrial morphology, oxygen consumption rate (OCR), fatty acid ß-oxidation (FAO) level, and ATP production were assessed. Additionally, fat transplantation and ASC-assisted fat transplantation model was treated with etomoxir which inhibits mitochondrial FAO. Macrophages pretreated with etomoxir were co-cultured with apoptotic adipocytes and treated with or without ASCs. The method aboved was used for detection and verification. RESULTS: In vivo, ASC-assisted fat transplantation improved macrophage mitochondrial expression and FAO level, promoted the early transformation of M2 macrophages, reduced the long-term lipid deposition of macrophages, and improved the retention rate of fat grafts. In vitro, ASCs up-regulated the level of mitochondrial FAO, OCR and ATP production in macrophages, reduced lipid deposition of macrophages and promoted M2 macrophages polarization by paracine function. The ability of ASCs in group pretreated with etomoxir to reduce the foaming of macrophages, promote the transformation to M2 macrophages, and improve the retention rate of fat transplantation was weakened. CONCLUSIONS: ASCs increased the retention rate of transplanted fat by upregulating mitochondrial FAO to promote M2 polaration in macrophages. In addition, ASCs up-regulate mitochondrial FAO by paracrine effect to reduce foam cells formation and promote M2 transformation in macrophages in vitro.

Effects of Obesity and Exercise on Hepatic and Pancreatic Lipid Content and Glucose Metabolism: PET Studies in Twins Discordant for BMI.

Obesity and sedentarism are associated with increased liver and pancreatic fat content (LFC and PFC, respectively) as well as impaired organ metabolism. Exercise training is known to decrease organ ectopic fat but its effects on organ metabolism are unclear. Genetic background affects susceptibility to obesity and the response to training. We studied the effects of regular exercise training on LFC, PFC, and metabolism in monozygotic twin pairs discordant for BMI. We recruited 12 BMI-discordant monozygotic twin pairs (age 40.4, SD 4.5 years; BMI 32.9, SD 7.6, 8 female pairs). Ten pairs completed six months of training intervention. We measured hepatic insulin-stimulated glucose uptake using [18F]FDG-PET and fat content using magnetic resonance spectroscopy before and after the intervention. At baseline LFC, PFC, gamma-glutamyl transferase (GT), and hepatic glucose uptake were significantly higher in the heavier twins compared to the leaner co-twins (p = 0.018, p = 0.02 and p = 0.01, respectively). Response to training in liver glucose uptake and GT differed between the twins (Time*group p = 0.04 and p = 0.004, respectively). Liver glucose uptake tended to decrease, and GT decreased only in the heavier twins (p = 0.032). In BMI-discordant twins, heavier twins showed higher LFC and PFC, which may underlie the observed increase in liver glucose uptake and GT. These alterations were mitigated by exercise. The small number of participants makes the results preliminary, and future research with a larger pool of participants is warranted.

Transcriptomic and Metabolomic Analysis Reveal the Effects of Light Quality on the Growth and Lipid Biosynthesis in Chlorella pyrenoidosa.

Light quality has significant effects on the growth and metabolite accumulation of algal cells. However, the related mechanism has not been fully elucidated. This study reveals that both red and blue light can promote the growth and biomass accumulation of Chlorella pyrenoidosa, with the enhancing effect of blue light being more pronounced. Cultivation under blue light reduced the content of total carbohydrate in Chlorella pyrenoidosa, while increasing the content of protein and lipid. Conversely, red light decreased the content of protein and increased the content of carbohydrate and lipid. Blue light induces a shift in carbon flux from carbohydrate to protein, while red light transfers carbon flux from protein to lipid. Transcriptomic and metabolomic analysis indicated that both red and blue light positively regulate lipid synthesis in Chlorella pyrenoidosa, but they exhibited distinct impacts on the fatty acid compositions. These findings suggest that manipulating light qualities can modulate carbon metabolic pathways, potentially converting protein into lipid in Chlorella pyrenoidosa.

Regulation of Oil Biosynthesis and Genetic Improvement in Plants: Advances and Prospects.

Triglycerides are the main storage form of oil in plant seeds. Both fatty acids and triglycerides possess important functions in the process of plant growth and development. To improve the seed oil content and improve its fatty acid composition, this paper analyzed the research progress on the oil regulation and synthesis metabolism process of plant seeds and summarized the strategies for the improvement of plant seed oil: (a) To regulate carbon distribution by inhibiting the expression of genes encoding key enzymes, allocating carbon sources into the protein synthesis pathway, and enhancing the expression of key genes encoding key enzymes, leading carbon sources into the synthesis pathway of fatty acids; (b) To intervene in lipid synthesis by promoting the biosynthesis of fatty acids and improving the expression level of key genes encoding enzymes in the triacylglycerol (TAG) assembly process; (c) To improve seed oil quality by altering the plant fatty acid composition and regulating the gene expression of fatty acid desaturase, as well as introducing an exogenous synthesis pathway of long chain polyunsaturated fatty acids; (d) To regulate the expression of transcription factors for lipid synthesis metabolism to increase the seed oil content. In addition, this article reviews the key enzymes involved in the biosynthesis of plant fatty acids, the synthesis of triacylglycerol, and the regulation process. It also summarizes the regulatory roles of transcription factors such as WRI, LEC, and Dof on the key enzymes during the synthesis process. This review holds significant implications for research on the genetic engineering applications in plant seed lipid metabolism.

Exploration of Genes Related to Intramuscular Fat Deposition in Xinjiang Brown Cattle.

The aim of this study was to investigate the differentially expressed genes associated with intramuscular fat deposition in the longissimus dorsi muscle of Xinjiang Brown Bulls. The longissimus dorsi muscles of 10 Xinjiang Brown Bulls were selected under the same feeding conditions. The intramuscular fat content of muscle samples was determined by the Soxhlet extraction method, for which 5 samples with high intramuscular fat content (HIMF group) and 5 samples with low intramuscular fat content (LIMF group) were selected. It was found that the intramuscular fat content of the HIMF group was 46.054% higher than that of the LIMF group. Muscle samples produced by paraffin sectioning were selected for morphological observation. It was found that the fat richness of the HIMF group was better than that of the LIMF group. Transcriptome sequencing technology was used to analyze the gene expression differences of longissimus dorsi muscle. Through in-depth analysis of the longissimus dorsi muscle by transcriptome sequencing technology, we screened a total of 165 differentially expressed genes. The results of Gene Ontology (GO) enrichment analysis showed that the differentially expressed genes in the two groups were mainly clustered in biological pathways related to carbohydrate metabolic processes, redox processes and oxidoreductase activities. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that the differentially expressed genes were significantly clustered in 15 metabolic pathways, which mainly covered fatty acid metabolism (related to lipid metabolism and glucose metabolism), the pentose phosphate pathway, the Peroxisome Proliferator-Activated Receptor (PPAR) signaling pathway and other important metabolic processes. The three genes that were predominantly enriched in the glycolipid metabolic pathway by analysis were SCD5, CPT1C and FBP2, all of which directly or indirectly affect intramuscular fat deposition. In summary, the present study investigated the differences in gene expression between high and low intramuscular fat content in the longissimus dorsi muscle of Xinjiang Brown Bulls by transcriptome sequencing technology and revealed the related signaling pathways. Therefore, we hypothesized that SCD5, CPT1C and FBP2 were the key genes responsible for the significant differences in intramuscular fat content of the longissimus dorsi muscles in a population of Xinjiang Brown Bulls. We expect that these findings will provide fundamental support for subsequent studies exploring key genes affecting fat deposition characteristics in Xinjiang Brown Bulls.

17α-Ethynylestradiol and Levonorgestrel Exposure of Rainbow Trout RTL-W1 Cells at 18 °C and 21 °C Mainly Reveals Thermal Tolerance, Absence of Estrogenic Effects, and Progestin-Induced Upregulation of Detoxification Genes.

Fish are exposed to increased water temperatures and aquatic pollutants, including endocrine-disrupting compounds (EDCs). Although each stressor can disturb fish liver metabolism independently, combined effects may exist. To unveil the molecular mechanisms behind the effects of EDCs and temperature, fish liver cell lines are potential models needing better characterisation. Accordingly, we exposed the rainbow trout RTL-W1 cells (72 h), at 18 °C and 21 °C, to ethynylestradiol (EE2), levonorgestrel (LNG), and a mixture of both hormones (MIX) at 10 µM. The gene expression of a selection of targets related to detoxification (CYP1A, CYP3A27, GST, UGT, CAT, and MRP2), estrogen exposure (ERα, VtgA), lipid metabolism (FAS, FABP1, FATP1), and temperature stress (HSP70b) was analysed by RT-qPCR. GST expression was higher after LNG exposure at 21 °C than at 18 °C. LNG further enhanced the expression of CAT, while both LNG and MIX increased the expressions of CYP3A27 and MRP2. In contrast, FAS expression only increased in MIX, compared to the control. ERα, VtgA, UGT, CYP1A, HSP70b, FABP1, and FATP1 expressions were not influenced by the temperature or the tested EDCs. The RTL-W1 model was unresponsive to EE2 alone, sensitive to LNG (in detoxification pathway genes), and mainly insensitive to the temperature range but had the potential to unveil specific interactions.

Overexpression of PER2 Promotes De Novo Fatty Acid Synthesis, Fatty Acid Desaturation, and Triglyceride Accumulation in Bovine Mammary Epithelial Cells.

The core clock gene Period2 (PER2) is associated with mammary gland development and lipid synthesis in rodents and has recently been found to have a diurnal variation in the process of lactation, but has not yet been demonstrated in bovine mammary epithelial cells (BMECs). To explore the regulatory function of PER2 on milk fat synthesis in bovine mammary epithelial cells, we initially assessed the expression of clock genes and milk fat metabolism genes for 24 h using real-time quantitative PCR and fitted the data to a cosine function curve. Subsequently, we overexpressed the PER2 in BMECs using plasmid vector (pcDNA3.1-PER2), with empty vector pcDNA3.1-myc as the control. After transfecting BMECs for 48 h, we assessed the protein abundance related to milk fat synthesis by Western blot, the expression of genes coding for these proteins using real time-quantitative PCR, the production of triacylglycerol, and the fatty acid profile. The findings indicated that a total of nine clock genes (PER1/2, CRY1/2, REV-ERBα, BMAL1, NCOR1, NR2F2, FBXW11), seven fatty acid metabolism genes (CD36, ACSS2, ACACA, SCD, FADS1, DGAT1, ADFP), and six nuclear receptor-related genes (INSIG1, SCAP, SREBF1, C/EBP, PPARG, LXR) exhibited oscillation with a period close to 24 h in non-transfected BMECs (R2 ≥ 0.7). Compared to the control group (transfected with empty pcDNA3.1-myc), the triglyceride content significantly increased in the PER2 overexpression group (p < 0.05). The lipogenic genes for fatty acid transport and triglyceride synthesis (ACACA, SCD, LPIN1, DGAT1, and SREBF1) were upregulated after PER2 overexpression, along with the upregulation of related protein abundance (p < 0.05). The contents and ratios of palmitic acid (C16:0), oleic acid (C18:1n9c), and trans-oleic acid (C18:1n9t) were significantly increased in the overexpression group (p < 0.05). Overall, the data supported that PER2 participated in the process of milk fat metabolism and is potentially involved in the de novo synthesis and desaturation of fatty acid in bovine mammary epithelial cells.

Exploring the role and therapeutic potential of lipid metabolism in acute kidney injury.

Acute kidney injury (AKI) is a prevalent condition, yet no specific treatment is available. Extensive research has revealed the pivotal role of lipid-related alterations in AKI. Lipid metabolism plays an essential role in the sustenance of the kidneys. In addition to their energy-supplying function, lipids contribute to the formation of renal biomembranes and the establishment of the renal microenvironment. Moreover, lipids or their metabolites actively participate in signal transduction, which governs various vital biological processes, such as proliferation, differentiation, apoptosis, autophagy, and epithelial-mesenchymal transition. While previous studies have focused predominantly on abnormalities in lipid metabolism in chronic kidney disease, this review focuses on lipid metabolism anomalies in AKI. We explore the significance of lipid metabolism products as potential biomarkers for the early diagnosis and classification of AKI. Additionally, this review assesses current preclinical investigations on the modulation of lipid metabolism in the progression of AKI. Finally, on the basis of existing research, this review proposes future directions, highlights challenges, and presents novel targets and innovative ideas for the treatment of and intervention in AKI.

Evaluating the therapeutic effect of different forms of silymarin on liver status and expression of some genes involved in fat metabolism, antioxidants and anti-inflammatory in older laying hens.

BACKGROUND: Silymarin, the predominant compound of milk thistle, is an extract took out from milk thistle (Silybum marianum) seeds, containing a mixture of flavonolignans with strong antioxidant capability. METHODS: The experiment was conducted using 70 Lohmann LSL-Lite hens at 80 weeks of age with 7 treatments each with 10 replicates. Treatments included: (1) control diet without silymarin, (2) daily intake of 100 mg silymarin powder/kg body weight (BW) (PSM100), (3) daily intake of 200 mg silymarin powder/kg BW (PSM200), (4) daily intake of 100 mg nano-silymarin/kg BW (NSM100), (5) daily intake of 200 mg nano-silymarin/kg BW (NSM200), (6) daily intake of 100 mg lecithinized silymarin/kg BW (LSM100) and (7) daily intake of 200 mg lecithinized silymarin/kg BW (LSM200). The birds were housed individually, and diets were fed for 12 weeks. RESULTS: Scanning electron microscopy showed that NSM was produced with the average particle size of 20.30 nm. Silymarin treatment improved serum antioxidant enzyme activity. All groups receiving silymarin showed a decrease in liver malondialdehyde content, expression of fatty acid synthase, tumour necrosis factor alpha, interleukin 6 (IL-6) genes in the liver, and hepatic steatosis than the control, except those fed the PSM100 diet. There were decreases in liver dry matter and fat contents, non-alcoholic fatty liver disease and hepatocyte ballooning, and an increase in glutathione peroxidase gene expression and a decrease in iNOS gene expression in birds fed the NSM100, NSM200, LSM100 and LSM200 diets compared to the control group. Moreover, all groups receiving silymarin showed a significant decrease in liver weight compare to the control group. CONCLUSIONS: Overall, the effects of silymarin when converted to NSM or LSM and offered at the level of 200 mg/kg BW were more pronounced on the hepatic variables and may be useful in the prevention of the liver disease in older laying hens.

Identification of genomic regions associated with fatty acid metabolism across blood, liver, backfat and muscle in pigs.

BACKGROUND: The composition and distribution of fatty acids (FA) are important factors determining the quality, flavor, and nutrient value of meat. In addition, FAs synthesized in the body participate in energy metabolism and are involved in different regulatory pathways in the form of signaling molecules or by acting as agonist or antagonist ligands of different nuclear receptors. Finally, synthesis and catabolism of FAs affect adaptive immunity by regulating lymphocyte metabolism. The present study performed genome-wide association studies using FA profiles of blood, liver, backfat and muscle from 432 commercial Duroc pigs. RESULTS: Twenty-five genomic regions located on 15 Sus scrofa chromosomes (SSC) were detected. Annotation of the quantitative trait locus (QTL) regions identified 49 lipid metabolism-related candidate genes. Among these QTLs, four were identified in more than one tissue. The ratio of C20:4n-6/C20:3n-6 was associated with the region on SSC2 at 7.56-14.26 Mb for backfat, liver, and muscle. Members of the fatty acid desaturase gene cluster (FADS1, FADS2, and FADS3) are the most promising candidate genes in this region. Two QTL regions on SSC14 (103.81-115.64 Mb and 100.91-128.14 Mb) were identified for FA desaturation in backfat and muscle. In addition, two separate regions on SSC9 at 0 - 14.55 Mb and on SSC12 at 0-1.91 Mb were both associated with the same multiple FA traits for backfat, with candidate genes involved in de novo FA synthesis and triacylglycerol (TAG) metabolism, such as DGAT2 and FASN. The ratio C20:0/C18:0 was associated with the region on SSC5 at 64.84-78.32 Mb for backfat. Furthermore, the association of the C16:0 content with the region at 118.92-123.95 Mb on SSC4 was blood specific. Finally, candidate genes involved in de novo lipogenesis regulate T cell differentiation and promote the generation of palmitoleate, an adipokine that alleviates inflammation. CONCLUSIONS: Several SNPs and candidate genes were associated with lipid metabolism in blood, liver, backfat, and muscle. These results contribute to elucidating the molecular mechanisms implicated in the determination of the FA profile in different pig tissues and can be useful in selection programs that aim to improve health and energy metabolism in pigs.

Proton Gradient Regulation 5 determines reserve partitioning between starch and lipids in C. reinhardtii.

Nutrient deprivation induces reserve accumulation in unicellular algae. An absence of nitrogen in the growth media results in the reorganization of the photosynthetic apparatus and triggers an increase in starch and triacylglyceride (TAG) accumulation in different algal species. Here we study the integration of photosynthetic regulatory mechanisms with carbon partitioning under N stress in C. reinhardtii. The mutant, proton gradient regulation 5 (pgr5) is impaired in photosynthetic cyclic electron flow resulting in low chloroplastic ATP/NADPH ratios. Over a time course, under both mixotrophic and phototrophic conditions, the pgr5 mutant did not accumulate starch in the first three days, but rather degraded its meagre reserves. In contrast, there was a high TAG content in the pgr5 mutant which we show, is not linked to a selective increase in autophagy in pgr5. In all strains, proteins involved in alternative electron pathways are upregulated while Photosystem II and chlorophyll are strongly degraded; pgr5 only preferentially preserved some cyt b6f complex. Our results show that low ATP/NADPH ratios due to an absence of cyclic electron flow in pgr5 result in the mobilization of starch and strong TAG accumulation from the onset of N stress in Chlamydomonas.

Involvement of a battery of investigated genes in lipid droplet pathophysiology and associated comorbidities.

Lipid droplets (LDs) are highly specialized energy storage organelles involved in the maintenance of lipid homoeostasis by regulating lipid flux within white adipose tissue (WAT). The physiological function of adipocytes and LDs can be compromised by mutations in several genes, leading to NEFA-induced lipotoxicity, which ultimately manifests as metabolic complications, predominantly in the form of dyslipidemia, ectopic fat accumulation, and insulin resistance. In this review, we delineate the effects of mutations and deficiencies in genes - CIDEC, PPARG, BSCL2, AGPAT2, PLIN1, LIPE, LMNA, CAV1, CEACAM1, and INSR - involved in lipid droplet metabolism and their associated pathophysiological impairments, highlighting their roles in the development of lipodystrophies and metabolic dysfunction.

Integrated bioinformatics analysis identifies PCSK9 as a prognosticator correlated with lipid metabolism in pancreatic adenocarcinoma.

BACKGROUND: Pancreatic adenocarcinoma (PAAD) is the most frequent kind of pancreatic cancer (PC). Recent studies suggest that lipid metabolism facilitates tumorigenesis, disease progression, and resistance to therapy by promoting lipid synthesis, accumulation, and breakdown. Thus, exploring the lipid metabolism network could unveil novel therapeutic avenues for early detection, precision medicine, and prognostication in PAAD. This project intends to develop new lipid metabolism-related biomarkers for PAAD diagnosis and investigate the link between important genes and immune cell infiltration (ICI). METHODS: Tissue samples from 20 PAAD patients and 20 healthy controls were obtained. Analysis were focused on the datasets GSE71729 and GSE16515, which include samples of PAAD (n = 161) and those from healthy human tissue (n = 61), derived from the GEO database. Knockdown of PCSK9 on PC cells were conducted by si-RNA and sh-RNA. Migration and cell functional experiments were performed to assess the role of PCSK9 in cell multiplication. Furthermore, a xenograft mouse model was employed to confirm PCSK9's function in vivo. RESULTS: The expression level of Proprotein convertase subtilisin/kexin type 9 (PCSK9) is significantly elevated in tissues affected by PAAD when compared to normal tissues. Survival analyses indicated that increased PCSK9 levels are inversely related to overall and disease-free survival (DFS). PCSK9's functional annotation associated it with the cell cycle and metabolism, especially energy metabolism. Examination of ICI data determined that PCSK9 expression demonstrated an unambiguous association with the M0 macrophages, T follicular helper cells (Tfh), gamma delta T cells and activated DC, and an inverse relationship with Monocytes, CD8+ T cells, memory B cells, resting CD4+ memory T cells, activated NK cells and resting DC abundance. PCSK9 expression knockdown has the ability to impede PC cells' migration and proliferation. CONCLUSION: Our study identified PCSK9 as a critical gene in PAAD. Expression levels of PCSK9 varied between PAAD and normal samples. ROC analysis verified PCSK9's strong capacity to differentiate PC from normal samples. Importantly, PCSK9 expression was considerably elevated in PC cell lines and tissues. Furthermore, PCSK9 stimulates the migration and proliferation of tumor cells in vivo and vitro.

Polyamine Pathway Inhibitor DENSPM Suppresses Lipid Metabolism in Pheochromocytoma Cell Line.

Pheochromocytomas (PCCs) are tumors arising from chromaffin cells in the adrenal medulla, and paragangliomas (PGLs) are tumors derived from extra-adrenal sympathetic or parasympathetic paraganglia; these tumors are collectively referred to as PPGL cancer. Treatment for PPGL primarily involves surgical removal of the tumor, and only limited options are available for treatment of the disease once it becomes metastatic. Human carriers of the heterozygous mutations in the succinate dehydrogenase subunit B (SDHB) gene are susceptible to the development of PPGL. A physiologically relevant PCC patient-derived cell line hPheo1 was developed, and SDHB_KD cells carrying a stable short hairpin knockdown of SDHB were derived from it. An untargeted metabolomic approach uncovered an overactive polyamine pathway in the SDHB_KD cells that was subsequently fully validated in a large set of human SDHB-mutant PPGL tumor samples. We previously reported that treatment with the polyamine metabolism inhibitor N1,N11-diethylnorspermine (DENSPM) drastically inhibited growth of these PCC-derived cells in culture as well as in xenograft mouse models. Here we explored the mechanisms underlying DENSPM action in hPheo1 and SDHB_KD cells. Specifically, by performing an RNAseq analysis, we have identified gene expression changes associated with DENSPM treatment that broadly interfere with all aspects of lipid metabolism, including fatty acid (FA) synthesis, desaturation, and import/uptake. Furthermore, by performing an untargeted lipidomic liquid chromatography-mass spectrometry (LC/MS)-based analysis we uncovered specific groups of lipids that are dramatically reduced as a result of DENSPM treatment. Specifically, the bulk of plasmanyl ether lipid species that have been recently reported as the major determinants of cancer cell fate are notably decreased. In summary, this work suggests an intersection between active polyamine and lipid pathways in PCC cells.

Ascochlorin Attenuates the Early Stage of Adipogenesis via the Wnt/ß-Catenin Pathway and Inhibits High-Fat-Diet-Induced Obesity in Mice.

This study investigated the effects of ascochlorin (ASC), a natural compound derived from the fungus Ascochyta viciae, on adipogenesis and obesity. We determined the effects of ASC on 3T3-L1 preadipocytes and whether it ameliorated to mitigate high-fat diet (HFD)-induced obesity in C57BL/6J mice. We found that ASC significantly inhibited the differentiation of preadipocytes by modulating the Wnt/ß-catenin signaling pathway, a key regulator of adipogenic processes. Treatment with ASC not only reduced the mRNA and protein expression of key adipogenic transcription factors such as C/EBPα and PPARγ, but also reduced lipid accumulation both in vitro and in vivo. In addition, treatment HFD-fed mice with ASC significantly reduced their weight gain and adiposity vs. control mice. These results suggest that ASC has considerable potential as a therapeutic agent for obesity, owing to its dual action of inhibiting adipocyte differentiation and reducing lipid accumulation. Thus, ASC represents a promising candidate as a natural anti-obesity agent.