Regulation Of Lipid Metabolism Research Articles

Integrated Transcriptome and Metabolomics Analysis Reveals That Probiotics and Tea Polyphenols Synergetically Regulate Lipid Metabolism in Laying Hens

Tea polyphenols (TP) and probiotics (PB) have been recognized for their ability to improve lipid metabolism and regulate immune function. However, their specific impact on lipid metabolism in laying hens has not been thoroughly elucidated. Therefore, this study sought to examine the effect of TP and Bacillus subtilis on lipid metabolism in laying hens through transcriptome and metabolome analyses. Two hundred Hy-line Brown layers were randomly allocated into four groups with supplemental dietary TP and PB alone and their combination for 8 weeks. Each treatment had 10 replicates of five birds. Supplementation with a TP and PB combination (TP-PB) increased redness (a*) (p < 0.05) compared to the control basal diet (CT). Dietary TP-PB decreased egg yolk and serum total cholesterol (TC) concentrations (p < 0.05) without affecting the content of total bile acid (TBA). The combined use of TP and PB significantly improved hepatic fatty acid synthetase (FAS) activity (p < 0.05) and reduced liver fat particles. Dietary TP-PB primarily influenced the transcript levels of genes involved in fat metabolic pathways. In particular, TP-PB supplementation reduced lipid storage by activating the Notch signaling pathway. Furthermore, the addition of TP-PB in the diet modulated the abundance of metabolic biomarkers associated with bile secretion and valine, leucine, and isoleucine degradation. An interaction network of mRNAs and metabolites was constructed associated with lipid metabolism, such as deoxycholic acid, TAG (14:3–14:3–20:5), PDK4, and HES4. Overall, these findings emphasized the potential health advantages of the TP and PB combination as a possible functional feed supplement in livestock nutrition.

Inhibition of PCSK9 Protects against Cerebral Ischemia‒Reperfusion Injury via Attenuating Microcirculatory Dysfunction.

Proprotein convertase substilin/kexin type 9 (PCSK9), a pivotal protein regulating lipid metabolism, has been implicated in promoting microthrombotic formation and inflammatory cascades, thereby contributing to cardiovascular ischemia/reperfusion (I/R) injury. However, its involvement in cerebral I/R injury and its potential role in microcirculation protection remain unexplored. In this investigation, we utilized a middle cerebral artery occlusion/reperfusion (MCAO/R) mouse model to simulate ischemic stroke. Different concentrations of evolocumab (1, 5, 10mg/kg, i.v.), a PCSK9 inhibitor, were administered to assess its impact. Immunofluorescence staining was employed to analyze changes in the expression of occludin, claudin-5, thrombocyte, ICAM-1, VCAM-1, and CD45, providing insights into blood-brain barrier integrity, platelet adhesion, and immune cell infiltration. Moreover, the Morris water maze and elevated plus maze were utilized to evaluate neurological and behavioral functions in MCAO/R mice, shedding light on the effects of PCSK9 inhibition. Our findings revealed a surge in plasma PCSK9 levels post-MCAO/R, peaking at 24h post-reperfusion. Evolocumab (10mg/kg) treatment significantly mitigated brain infarction and neurological deficits, evidenced by enhanced locomotor function and reduced post-stroke anxiety. However, it did not ameliorate cognitive impairment following MCAO/R. Additionally, evolocumab administration led to diminished leakage of evans blue solution and upregulated expression of occludin and claudin-5. Thrombocyte, ICAM-1, VCAM-1, and CD45 levels were notably reduced in the penumbral area post-evolocumab treatment. These protective effects are speculated to be mediated through the inhibition of the ERK/NF-κB pathway. The PCSK9 inhibitor evolocumab holds promise as a therapeutic agent during the acute phase of stroke, exerting its beneficial effects by modulating the ERK/NF-κB signaling pathway.

Lingguizhugan decoction alleviates obesity in rats on a high-fat diet through the regulation of lipid metabolism and intestinal microbiota

BackgroundIndividuals with obesity often experience elevated blood lipid levels, leading to a chronic low-grade inflammatory state, exacerbating liver oxidative stress, and increasing the risk of various metabolic diseases. Recent evidence suggests that intestinal microbiota and short-chain fatty acids (SCFAs) play crucial roles in the development and progression of obesity. While the mechanisms by which Lingguizhugan decoction (LGZGD) intervenes in obesity by improving lipid metabolism, enhancing insulin sensitivity, and reducing inflammatory responses are well-documented, its potential in intestinal microbiota and SCFAs remains unclear. This study aims to explore the impact of LGZGD on high-fat diet (HFD) induced obesity in rats and its regulatory effects on intestinal microbiota and SCFAs, providing new insights for obesity prevention and treatment.MethodsFifty-one male SD rats were randomly divided into groups, with six in the normal control group (NC) receiving a ddH2O treatment and a standard diet. The remaining 45 rats were fed a high-fat diet (HFD) using D12451 feed. After 10 weeks, the rats on the HFD gained 20% more weight than the NC group, confirming the successful modeling of obesity. These rats were then randomly divided into the following groups: ddH2O high-fat diet model group (MC), 20 mg/kg/day Orlistat positive control group (Orlistat), 1.62 g/kg/day low-dose LGZGD group (LGZGL), and 3.24 g/kg/day high-dose LGZGD group (LGZGH) for 8 weeks. We evaluated changes in body weight, serum total cholesterol (TC), total triacylglycerol (TG), low-density lipoprotein cholesterol (LDL), and high-density lipoprotein cholesterol (HDL) levels. Fat and liver tissues were collected for pathological analysis. Intestinal contents were aseptically collected for 16S rRNA gene sequencing and gas chromatography–mass spectrometry (GC–MS) to assess gut microbiota and SCFA levels.ResultsLGZGD reduces body weight, TC, TG, LDL, and HDL levels, significantly reducing hepatic steatosis. Besides, it restored the richness and diversity of gut microbiota, which was reduced by HFD, altering the overall structure. Specifically, LGZGD significantly promoted the growth of Muribaculaceae and Dubosiella while inhibiting the growth of Christensenellaceae_R_7_group and UCG_005. It also restricts the production of caproic acid. Correlation analysis indicated positive correlations: Muribaculaceae with Butyric acid and Isovaleric acid; UCG_005 with TC, LDL, and HDL; and Christensenellaceae_R_7_group with TC and LDL.ConclusionLGZGD increased the abundance of beneficial gut microbiota in HFD-induced obese rats, improved gut microbiota dysbiosis, and inhibited the increase in caproic acid content. These results suggest that LGZGD can mitigate HFD-induced obesity, and its active components warrant further investigation.

Investigating the Role of Inositol: Myo-inositol and D-Chiro-inositol in Diabetes: A Review

The sugar alcohol known as inositol and its derivatives are becoming more and more interesting in metabolism-related research studies due to its physiological roles. Inositol derivatives mainly myoinositol and d-chiroinositol have gained so much attention these days in the context of managing and treating metabolic issues such as diabetes and polycystic ovarian syndrome. For a long time, it was considered as the vitamin B, but later we got to know it is produced from glucose so considered non-essential. Nowadays rising rates of obesity which are further linked with diabetes and polycystic ovarian syndrome have fuelled demand for artificial sweeteners. Many people are searching for options to maintain their weight, which has led to the widespread usage of sucrose and fructose substitutes in the food industry. Sugar alcohols such as myoinositol and d chiroinositol (which are not been commonly used) in particular can be metabolized without the need for insulin control and have little effect on blood sugar levels. These sugar substitutes have the potential to provide sweetness without raising blood sugar levels and adding calories. These have half of the sweetness of sucrose. This paper aims to thoroughly investigate and understand the various roles played by inositol in the complex field of managing metabolic diseases. To find out the eligible papers for review paper screening has been performed through PubMed, Science Direct, Web of Science and Google Scholar. Different sets of keywords such as inositol, d chiro inositol, myo-inositol, insulin-resistance, diabetes, insulin sensitivity, DCI and type 2 diabetes mellitus were used. Studies which full text article were present used for the review. Research articles have been included the studies specifically to find out the relation between myoinositol and diabetes or any metabolic disease. The development of many diseases, such as PCOS and diabetes, is linked with inositol deficiency. Myoinositol is derived from the food we eat as well as from within. The low levels of MI can be the result of several factors, including decreased dietary intake, increased catabolism, alterations in the gut and reduced biosynthesis. These two forms, myoinositol and d-chiroinositol play significant roles in regulating lipid metabolism and glycaemic control. glycaemic metabolism and this are also supported by many research studies. Therefore, it can be a possible treatment or management option for people suffering from metabolic issues such as diabetes and PCOS. Future studies should focus on how we can increase the intake of myoinositol through diet and dietary food products.

Epidermal maintenance of Langerhans cells relies on autophagy-regulated lipid metabolism.

Macroautophagy (often-named autophagy), a catabolic process involving autophagy-related (Atg) genes, prevents the accumulation of harmful cytoplasmic components and mobilizes energy reserves in long-lived and self-renewing cells. Autophagy deficiency affects antigen presentation in conventional dendritic cells (DCs) without impacting their survival. However, previous studies did not address epidermal Langerhans cells (LCs). Here, we demonstrate that deletion of either Atg5 or Atg7 in LCs leads to their gradual depletion. ATG5-deficient LCs showed metabolic dysregulation and accumulated neutral lipids. Despite increased mitochondrial respiratory capacity, they were unable to process lipids, eventually leading them to ferroptosis. Finally, metabolically impaired LCs upregulated proinflammatory transcripts and showed decreased expression of neuronal interaction receptors. Altogether, autophagy represents a critical regulator of lipid storage and metabolism in LCs, allowing their maintenance in the epidermis.

Estrogen Regulates Mitochondrial Activity Through Inducing Brain-Derived Neurotrophic Factor Expression in Skeletal Muscle.

Estrogen is an essential hormone for the development and functional activities of reproductive organs. Recent studies showed that estrogen signaling is also an important regulator of lipid and glucose metabolism in a number of tissues, but the molecular mechanism is not fully understood. We report here that estrogen is a stimulator of brain-derived neurotrophic factor (BDNF) synthesis in the skeletal muscle. Estradiol (E2), but not testosterone, induces a dose- and time-dependent BDNF production in cultured myotubes. Estrogen depletion in ovariectomized mice significantly reduced Bdnf expression in the glycolytic myofibers, which could be rescued after E2 administration. Mechanistically, E2 stimulation triggered the tethering of estrogen receptor (ER) α, but not ERβ, to the estrogen-responsive element on promoter VI of the Bdnf gene in skeletal muscle. When Bdnf production was inhibited by shRNA in C2C12 myotubes, E2-induced mitochondria activation and pyruvate dehydrogenase kinase 4 expressions were jeopardized. Collectively, our results demonstrate that BDNF is an underrecognized effector of estrogen in regulating mitochondrial activity and fuel metabolism in the skeletal muscle.

Abstract 4146303: A Single-Dose of a Novel CasX-Editor Lowers APOC3 Levels In Vivo

Background: Apolipoprotein C-III (APOC3) is a key regulator of lipid metabolism that inhibits the catabolism and clearance of triglyceride (TG)-rich lipoproteins in the blood. Loss-of-function APOC3 variants are associated with significantly lower TG levels and a reduced risk of heart disease, underscoring the potential of APOC3 inactivation as a therapeutic strategy for patients with familial chylomicronemia syndrome (FCS) and severe hypertriglyceridemia (SHTG). Here, we developed STX-1400 lead molecules as a novel investigational gene editing treatment using a highly engineered CRISPR-CasX mRNA and a guide RNA (gRNA) encapsulated into lipid nanoparticles (LNPs) to edit the APOC3 gene and knock out its hepatic expression. Methods: STX-1400 lead molecules were evaluated for editing potency and resulting functional effects on APOC3 reduction in vitro in primary human hepatocytes (PHHs) and primary cynomolgus hepatocytes (PCHs). In vivo studies were conducted in PXB mice, a humanized liver mouse model. Liver biopsies and serum samples were collected at two weeks post-dose. Human APOC3 mRNA and APOC3 protein levels were measured in liver biopsies and serum samples, respectively. Lipid profile evaluation, which included measuring TGs and total cholesterol (TC) levels, was also performed. Results: Treatment of PHHs with LNPs containing STX-1400 lead molecules showed a dose-dependent increase in editing activity; up to 90% editing at the APOC3 locus was associated with >70% reduction in secreted APOC3 protein levels. Potency was also observed in PCHs, with up to 70% editing. A single dose of LNPs encapsulating STX-1400 lead molecules delivered into PXB humanized mice resulted in >60% editing at the APOC3 locus in the liver, which was associated with >90% reduction of serum hAPOC3 protein levels, accompanied by reduction in TG and TC levels. Conclusions: These data demonstrate that the STX-1400 lead molecules efficiently knock down hepatic expression of APOC3 in preclinical models. This work suggests that the CRISPR-CasX-based editor approach could be developed as a single dose therapy for the treatment of hypertriglyceridemia.

Lactiplantibacillus plantarum Y44 Complex Fermented Milk Regulates Lipid Metabolism in Mice Fed with High-Fat Diet by Modulating Gut Microbiota.

The benefits of fermented milk containing Lactiplantibacillus plantarum (L. plantarum) Y44, known for its weight loss properties, remain unclear. For this, we evaluated the effects of the complex fermented milk (Y44-CFM), obtained through the cofermentation of cow's milk and soybean milk with L. plantarum Y44 and traditional starters, on high-fat diet (HFD)-fed C57BL/6 mice. Our study found that the oral administration of Y44-CFM significantly reduced body weight gain and hepatic lipid accumulation in HFD-fed mice while also mitigating liver injury. Additionally, Y44-CFM regulated the expression of enzymes associated with lipid metabolism in the serum, as well as the corresponding or related genes in the liver, such as fatty acid synthase. Furthermore, HFD-induced systemic inflammation, oxidative stress, and intestinal barrier dysfunction were improved. The primary alterations in hepatic metabolism involved glycerophospholipids and amino acids, including the biosynthesis of valine, leucine, and isoleucine. The diversity and overall structure of the gut microbiota were also regulated, resulting in a significant decrease in the ratio of Firmicutes to Bacteroidetes (F/B) and unclassified_f_Lachnospiraceae, along with a notable increase in Oscillospiraceae. The correlation analysis indicated that Y44-CFM influenced hepatic lipid metabolism by mediating intestinal flora and its production of short-chain fatty acids, ultimately leading to weight reduction.

TMET-33. INVESTIGATING THE ROLE OF CHEMERIN SIGNALING IN GLIOBLASTOMA

Abstract Glioblastoma multiforme (GBM) is one of the most common and lethal primary brain tumors in adults. Despite clinical efforts, patient prognosis remains poor with a median survival of approximately 14 months. Thus, identification of novel treatment avenues is needed. Metabolic rewiring is a hallmark of cancer and lipid homeostasis has an increasingly appreciated role in cancer cell survival. It has been shown that the disruption of lipid metabolic balance can lead to lipotoxicity, creating a new avenue in GBM treatment. Therefore, identifying methods to disrupt said lipid metabolic balance in GBM could provide a needed foothold. Previous studies from the lab have identified chemerin, a multifunctional adipokine encoded by the retinoic acid receptor responder 2 (RARRES2) gene, as an important and targetable lipid metabolism modulator in Clear cell renal cell carcinoma (ccRCC). Chemerin has also been implicated in the mesenchymal-phenotype promoting network between GBM cells and tumor-associated macrophages. Given similarities in GBM and ccRCC lipid metabolism and the existing role of chemerin in the tumor immune microenvironment in GBM, we hypothesize that chemerin drives GBM development by regulating lipid metabolism in addition to immune cell trafficking. This study aims to investigate the role and therapeutic opportunities of altered lipid metabolism in GBM by examining chemerin and its receptors (CMKLR1 and GPR1). Immunocompetent GBM mouse models generated through CRISPR-in utero electroporation (IUE) show that mice bearing RARRES2, CMKLR1, and GPR1 knockout tumors have prolonged survival. In addition, in vitro molecular inhibition of CMKLR1 in both human and murine GBM cell lines results in cell death. Ongoing studies involving in vitro CRISPR knockouts of RARRES2, CMKLR1, and GPR1 aim to elucidate the mechanisms by which in vivo inhibition of chemerin signaling results in slower tumor progression.

Molecular mechanisms of lipid droplets-mitochondria coupling in obesity and metabolic syndrome: insights and pharmacological implications

Abnormal lipid accumulation is a fundamental contributor to obesity and metabolic disorders. Lipid droplets (LDs) and mitochondria (MT) serve as organelle chaperones in lipid metabolism and energy balance. LDs play a crucial role in lipid storage and mobilization, working in conjunction with MT to regulate lipid metabolism within the liver, brown adipose tissue, and skeletal muscle, thereby maintaining metabolic homeostasis. The novelty of our review is the comprehensive description of LD and MT interaction mechanisms. We also focus on the current drugs that target this metabolism, which provide novel approaches for obesity and related metabolism disorder treatment.

The Role of Exosomal miRNAs in Regulating Lipid Metabolism in Obesity-Associated Hyperlipidemia

Obesity-associated hyperlipidemia is a major risk factor for cardiovascular diseases, metabolic syndrome, and other complications. The dysregulation of lipid metabolism in obesity is driven by a complex network of molecular and cellular mechanisms. Among these, exosomal microRNAs (miRNAs) have emerged as key regulators in the communication between adipose tissue, the liver, and other metabolic organs. Exosomes, small vesicles secreted by various cell types, contain miRNAs that can modulate gene expression in recipient cells, thereby influencing lipid metabolism. This review explores the role of exosomal miRNAs in obesity-associated hyperlipidemia, focusing on their mechanisms of action, regulatory functions, and potential therapeutic implications. We highlight specific exosomal miRNAs involved in lipid metabolism pathways, their role in adipogenesis, lipogenesis, and lipid storage, as well as their impact on systemic lipid homeostasis. Additionally, we discuss the potential of targeting exosomal miRNAs as a novel therapeutic approach for managing hyperlipidemia and obesity-related metabolic disorders. Keywords: exosomal miRNAs, lipid metabolism, obesity, hyperlipidemia, adipogenesis, lipogenesis, therapeutic targeting

Berberine Mediates Exosomes Regulating the Lipid Metabolism Pathways to Promote Apoptosis of RA-FLS Cells

Objectives: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint damage and commonly linked to symptoms such as inflammation, swelling, and pain. Traditional Chinese Medicine offers complementary and integrative approaches in the management of rheumatoid arthritis, potentially providing additional options that may help address treatment challenges and enhance overall patient care. This paper explores the mechanism of action of berberine from the perspective of cellular exosomes by mediating exosomal contents and thus treating RA. Methods: With the help of flow cytometry and confocal laser scanning microscope, it was determined that berberine promotes apoptosis in RA-FLS cells, and then lipid metabolomics technology was applied to screen and characterize the exosomes of RA-FLS cells to identify lipid core biomarkers closely related to RA, which were then projected into various databases for comprehensive analysis. Results: The data analysis showed that berberine could call back 11 lipid core biomarkers closely associated with RA, and interactive visualization of the database revealed that these markers were mainly focused on lipid metabolism aspects such as fatty acid elongation, degradation, and biosynthesis, as well as the biosynthesis of unsaturated fatty acids or PPARA activation of gene expression, PPARα‘s role in lipid metabolism regulation, glycerophospholipid metabolism, mitochondrial fatty acid oxidation disorders, and organelle biogenesis and maintenance. Conclusions: Berberine exerts its therapeutic effect on RA by mediating exosomal contents and thus regulating multiple lipid-related biological pathways, affecting the PPARγ-NF-κB complex binding rate, CREB and EGR-1 expression, cellular phagocytosis, and other aspects needed to inhibit proliferation and inflammatory responses in RA-FLS. This study offers a research foundation for exploring the mechanism of action of berberine in the treatment of RA.

Lipid metabolism and food ingredients from the perspective of thermogenic adipocytes.

The high heat-producing capacity of brown and beige adipocytes, collectively known as thermogenic adipocytes, contributes to whole-body energy expenditure and is an attractive target for the management of obesity. It has been revealed that the functions of thermogenic adipocytes are important for the regulation of whole-body carbohydrate and lipid metabolism, and the activation of thermogenic adipocytes seems to have beneficial effects for the management of obesity-related metabolic disorders, such as dyslipidemia. Recent studies have showed that specific food ingredients have the potential to activate thermogenic adipocytes via various mechanisms. Some of these are effective not only in rodents, but also in humans, and effective prevention of obesity using these food ingredients is expected. In this review, we introduce the recent findings on the regulatory mechanisms of lipid metabolism by thermogenic adipocytes and food ingredients, demonstrating the potential to activate thermogenic adipocytes and their underlying mechanisms.

Relationship between thyroid-stimulating hormone and blood lipids in patients with first-episode depression

BackgroundPrevious studies demonstrated thyroid stimulating hormone (TSH) plays an important role in regulating lipid metabolism, but the relationship between the two is controversial. Meanwhile, it has not been reported in a population with major depressive disorder (MDD).MethodsWe divided 1718 first-episode and drug naïve patients with MDD into a TSH abnormal group (TSH-AB) and a TSH normal group (TSH-NOR). The participants in the two groups were assessed by the Hamilton Depression Rating Scale (HAMD), Hamilton Anxiety Rating Scale (HAMA) and the positive subscale of Positive and Negative Syndrome Scale. The patients’ blood was tested for TSH, free T3, free T4, fasting blood glucose, lipid indexes and body mass index was recorded.ResultsThe participants in the TSH-AB group had significantly higher HAMD scores, HAMA scores and total scores of positive symptoms, as well as higher incidence of suicide attempts than those in the TSH-NOR group, accompanied by significantly higher thyroglobulin antibodies, thyroid peroxidase antibodies, fasting blood glucose values, total cholesterol (TC), triglycerides (TG) and low-density lipoprotein cholesterol (LDL-C) levels compared with those of TSH-NOR patients. However, the high-density lipoprotein cholesterol (HDL-C) of TSH-AB patients was lower than those of TSH-NOR patients. TSH values were positively correlated with TC, TG, and LDL-C values, and negatively correlated with HDL-C value.ConclusionTSH was highly correlated with abnormal lipid metabolism in patients with MDD. The specific molecular mechanism of the relationship between TSH, lipid metabolism and the development of depression needs to be further in-depth investigation.

Targeting the Renin-Angiotensin System in Obesity-Driven Hyperlipidemia and Hypertension

The renin-angiotensin system (RAS) plays a crucial role in the regulation of blood pressure, fluid balance, and lipid metabolism. Dysregulation of the RAS has been implicated in the pathogenesis of obesity-driven hyperlipidemia and hypertension, two major components of metabolic syndrome that significantly increase the risk of cardiovascular disease. In obese individuals, increased adipose tissue promotes local activation of the RAS, leading to heightened angiotensin II (Ang II) activity, oxidative stress, inflammation, and impaired lipid metabolism. These pathological mechanisms contribute to both elevated blood pressure and abnormal lipid profiles. Targeting the RAS through angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and novel agents offers therapeutic potential in reducing obesity-associated hypertension and hyperlipidemia. This review discusses the molecular mechanisms linking obesity to RAS overactivation, examines current pharmacological strategies, and explores emerging therapeutic options aimed at modulating the RAS in the context of obesity-driven cardiometabolic disorders. Keywords: Renin-angiotensin system, obesity, hyperlipidemia, hypertension, angiotensin II, ACE inhibitors, ARBs, metabolic syndrome, cardiovascular disease.

PPARs: modulating lipotoxicity and thus inhibiting fibrosis.

Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone receptor family of ligand-activated receptors and are known for their roles as key factors in the regulation of lipid metabolism. In the more than three decades since their discovery, most reports on PPARs have focused on their roles in lipid metabolism, and a portion of the new research has also focused on the relationship between PPARs and fibrosis. Interestingly, lipid metabolism disorders and fibrosis are also inextricably linked. This implies that PPARs, lipid metabolism and fibrosis are interrelated. On this basis, we have summarized the molecular mechanisms of PPARs regulating fibrosis through lipid metabolism and PPARγ directly regulating fibrosis, and pointed out the contradictions and enigmas that need to be further explored in the processes of PPARs regulating lipid metabolism and fibrosis. The aim of the present review is to provide new ideas for PPARs for the treatment of lipid metabolism disorders and fibrosis.

Peroxisome proliferator-activated receptor agonists as an adjuvant for cancer therapy: A review

Cancer is now one of the leading diseases responsible for the highest mortality rates worldwide. Cancer treatment is extremely intricate and is often associated with less targeted effects and more side effects. In the last few years, two significant revolutions in cancer treatment have altered treatment paradigms: immuno-oncology and the pursuit of actionable changes in oncogene-driven cancers. Significant obstacles continue to exist in both areas of cancer treatment. Next-generation sequencing technologies for molecular prescreening in clinical research are advancing, but their widespread clinical use is hindered by challenges related to the clinical interpretation of large genomic data. Moreover, cancer mono-chemotherapy is associated with issues such as inadequate efficacy, drug resistance, and systemic toxicity. It is not possible to administer cytotoxic drugs limitlessly. Combination therapy was developed in response to this circumstance, with the expectation of achieving high therapeutic efficacy at lower dosages of medication. Peroxisome proliferator-activated receptors (PPARs) are a group of essential lipid sensors and metabolic pathway regulators. In addition, they possess the ability to modulate immunity, inflammation, and endothelial nitric oxide synthase activation. Alongside their well-established functions, new insights into the roles of PPAR agonists in cancer research are emerging. After reviewing current research, it is evident that PPAR modulators have significant potential for managing cancer. This review aims to consolidate the functions of PPAR ligands alongside other cancer therapies. We provide a comprehensive perspective on the applicability of PPAR ligands in cancer treatment as an adjuvant.

PTPRK regulates glycolysis and de novo lipogenesis to promote hepatocyte metabolic reprogramming in obesity

Fat accumulation, de novo lipogenesis, and glycolysis are key drivers of hepatocyte reprogramming and the consequent metabolic dysfunction-associated steatotic liver disease (MASLD). Here we report that obesity leads to dysregulated expression of hepatic protein-tyrosine phosphatases (PTPs). PTPRK was found to be increased in steatotic hepatocytes in both humans and mice, and correlates positively with PPARγ-induced lipogenic signaling. High-fat-fed PTPRK knockout male and female mice have lower weight gain and reduced hepatic fat accumulation. Phosphoproteomic analysis in primary hepatocytes and hepatic metabolomics identified fructose-1,6-bisphosphatase 1 and glycolysis as PTPRK targets in metabolic reprogramming. Mechanistically, PTPRK-induced glycolysis enhances PPARγ and lipogenesis in hepatocytes. Silencing PTPRK in liver cancer cell lines reduces colony-forming capacity and high-fat-fed PTPRK knockout mice exposed to a hepatic carcinogen develop smaller tumours. Our study defines the role of PTPRK in the regulation of hepatic glycolysis, lipid metabolism, and tumour development in obesity.

Rab2A-mediated Golgi-lipid droplet interactions support very-low-density lipoprotein secretion in hepatocytes.

Lipid droplets (LDs) serve as crucial hubs for lipid trafficking and metabolic regulation through their numerous interactions with various organelles. While the interplay between LDs and the Golgi apparatus has been recognized, their roles and underlying mechanisms remain poorly understood. Here, we reveal the role of Ras-related protein Rab-2A (Rab2A) in mediating LD-Golgi interactions, thereby contributing to very-low-density lipoprotein (VLDL) lipidation and secretion in hepatocytes. Mechanistically, our findings identify a selective interaction between Golgi-localized Rab2A and 17-beta-hydroxysteroid dehydrogenase 13 (HSD17B13) protein residing on LDs. This complex facilitates dynamic organelle communication between the Golgi apparatus and LDs, thus contributing to lipid transfer from LDs to the Golgi apparatus for VLDL2 lipidation and secretion. Attenuation of Rab2A activity via AMP-activated protein kinase (AMPK) suppresses the Rab2A-HSD17B13 complex formation, impairing LD-Golgi interactions and subsequent VLDL secretion. Furthermore, genetic inhibition of Rab2A and HSD17B13 in the liver reduces the serum triglyceride and cholesterol levels. Collectively, this study provides a new perspective on the interactions between the Golgi apparatus and LDs.

MRG15 promotes cell apoptosis through inhibition of mitophagy in hyperlipidemic acute pancreatitis.

Hyperlipidemia is a common cause of acute pancreatitis (AP), often leading to more severe clinical symptoms. The mortality factor 4-like protein 1 (MORF4L1, also called MRG15) plays a crucial role in regulating lipid metabolism. Therefore, this study aimed to explore the mechanism of MRG15 in hyperlipidemic acute pancreatitis (HAP). Mendelian randomization, transcriptome analysis, and single-cell analysis were employed to explore the association between MRG15 and AP by utilizing publicly available databases. In vivo, hypertriglyceridemia mouse models were created by intraperitoneal injection of P407 or using APOE-deficient mice. Subsequently, the HAP model was induced by cerulean. In vitro, a cell model of HAP was established by initially exposing cells to palmitic acid to simulate a high-fat environment, followed by cerulein treatment. Subsequently, MRG15-related indicators were measured. Through Mendelian randomization, it was discovered that there is a positive correlation between genetic expression of MRG15 and the risk of AP. Transcriptome and single-cell analysis revealed that elevated MRG15 expression in AP contributes to lipid metabolism disorders and the activation of apoptosis pathways in pancreatic acinar cells. MRG15 is found to be significantly upregulated in cases of HAP. Knocking down MRG15 led to an increase in mitophagy and a decrease in apoptosis in pancreatic cells, and this effect was reversed when the mitochondrial Tu translation elongation factor (TUFM) was simultaneously knocked down. MRG15 inhibits mitophagy by degrading TUFM, ultimately promoting cell apoptosis and worsening the progression of HAP.