Increased Lipid Synthesis Research Articles

High mobility group A1 (HMGA1) promotes the tumorigenesis of colorectal cancer by increasing lipid synthesis.

Metabolic reprogramming is a hallmark of cancer, enabling tumor cells to meet the high energy and biosynthetic demands required for their proliferation. High mobility group A1 (HMGA1) is a structural transcription factor and frequently overexpressed in human colorectal cancer (CRC). Here, we show that HMGA1 promotes CRC progression by driving lipid synthesis in a AOM/DSS-induced CRC mouse model. Using conditional knockout (Hmga1△IEC) and knock-in (Hmga1IEC-OE/+) mouse models, we demonstrate that HMGA1 enhances CRC cell proliferation and accelerates tumor development by upregulating fatty acid synthase (FASN). Mechanistically, HMGA1 increases the transcriptional activity of sterol regulatory element-binding protein 1 (SREBP1) on the FASN promoter, leading to increased lipid accumulation in intestinal epithelial cells. Moreover, a high-fat diet exacerbates CRC progression in Hmga1△IEC mice, while pharmacological inhibition of FASN by orlistat reduces tumor growth in Hmga1IEC-OE/+ mice. Our findings suggest that targeting lipid metabolism could offer a promising therapeutic strategy for CRC.

Age-Related Increases in IGFBP2 Increase Melanoma Cell Invasion and Lipid Synthesis.

The aged microenvironment drives metastasis in melanoma cells. This study reports that IGFBP2 secretion by aged fibroblasts induces lipid accumulation in melanoma cells, driving an increase in tumor invasiveness. Neutralizing IGFBP2 decreases melanoma tumor growth and metastasis.

Regulation of AreA on lipid biosynthesis under different nitrogen sources and C/N ratios in the model oleaginous fungus Mucor circinelloides

Mucor circinelloides has been exploited as model filamentous fungi for studies of genetic manipulation of lipogenesis. It is widely recognized that lipid accumulation is increased when there is a lack of nitrogen source in oleaginous microorganism. Nitrogen metabolism in filamentous fungi is a complex process that can be regulated by the global nitrogen regulator AreA. In this study, we cultivated the areA-knockout and -overexpression strains obtained in our previous study, using 20 different nitrogen sources. It emerged that the disruption of AreA in M. circinelloides reduced its sensitivity to nitrogen availability, resulting in increased lipid synthesis. Specially, the areA-knockout strain was unable to fully utilize many nitrogen sources but the ammonium and glutamate. We continued to investigate lipid production at different molar C/N ratios using glucose as sole carbon source and ammonium sulfate as sole nitrogen source, of which the high C/N ratios activate high lipid accumulation. By comparing the experimental results with transcriptional analysis, we were able to identify the optimal process conditions suitable for lipid accumulation and potential targets for future metabolic engineering.

Abstract PO4-04-09: Incidence, prevalence, risk factors, and impact of fatty liver disease in metastatic HR+/HER2− breast cancer patients treated with Endocrine Therapy and CDK 4/6 Inhibitor

Abstract Background: In patients with early-stage breast cancer (BC), non-alcoholic fatty liver disease (NAFLD) is associated with increased recurrence, cardiovascular events, and non-cancer death. Endocrine therapy increases the risk of NAFLD. The impact of cyclin-dependent kinases 4/6 inhibitors (CDKi) combined with endocrine therapy on NAFLD and prognostic association in metastatic breast canceris unknown. Here, we characterize the incidence, prevalence, risk factors, and treatment outcomes of NAFLD in women with metastatic HR+/HER2- BC. Methods: We conducted a retrospective cohort study of patients with advanced HR+/HER2- BC receiving first line endocrine and CDKi at Princess Margaret Cancer Centre, Toronto, Canada between January 2018 – June 2022. Patients were excluded if they had liver disease, prior chemotherapy, or no access to CT scans. Demographic, treatment, toxicity, and survival data were extracted. Liver Attenuation Index (LAI) on contrast-enhanced portal venous phase CT scan was utilized.NAFLD was defined as LAI >25 HU. Univariable binary-logistic regression analysis wasused to assess independent predictive factors of NAFLD. Statistical significance was defined as p< 0.05. Quantitative significance was defined by the Burnand criteria. Time to treatment failure (TTF) was assessed using Cox proportional hazards modeling. Results: Of approximately 90 eligible patients, 40 are included in this analysis. Baseline demographics included median age 61 years, 72% post-menopausal, 58% de-novo metastatic disease, and 27% visceral disease. Of 40 patients, 28 (70%) had NAFLD at anytime (12 at baseline and 16 incident). Associations with NAFLD are shown in Table 1. Presence of NAFLD was associated quantitatively but not statistically with age > 65 (OR 2.6), post-menopausal status (OR 2.6), and inversely associated with prior chemotherapy (OR 0.27) and visceral disease (OR 0.38). Lack of NAFLD at any time was significantly associated with worse TTF (mean TTF 497 versus 1228 days, HR=4.28, 95% CI: 1.89-9.68, p< 0.001). Patients without NAFLD at baseline also had a worse TTF (mean 903 vs 1186 days) compared to those with it at baseline, but this difference was not statistically significance (HR=1.93, 95%CI: 0.77-4.83, p= 0.163). No significant differences were found in grade 3/4 adverse events. Patients who have presented NAFLD at any time received an average of 1.36 subsequent lines of therapy compared to 2.08 in those without. Discussion & Conclusion: This analysis demonstrated an association between presence of NAFLD and longer TTF. This may reflect reverse causation whereby longer exposure to ET and CDKi increases the observation of NAFLD or that these are distinct populations with different molecular pathways leading to differences in response to treatment and prognosis. It is noteworthy that the median time to develop NAFLD in the incident group was 339 days, and the group that never developed NAFLD was on treatment longer than this. Overexpression of CDK 4/6 pathway, could increase sensitivity and duration to treatment with CDKi but produce adverse metabolic changes of increased lipid synthesis, as described in pre-clinical models. If this hypothesis is confirmed, synergistically addressing these metabolic changes with physical exercise, dietary, or pharmacological interventions may improve these patients’ fitness for subsequent lines of therapy. Table 1 Citation Format: Diego Malon Gimenez, Consolacion Molto Valiente, Shopnil Prasla, Danielle Cuthbert, Abhenil Mittal, Faris Tamimi, Massimo Di Iorio, Meredith Li, Neha Pathak, Eitan Amir, Kartik Jhaveri, Michelle Nadler. Incidence, prevalence, risk factors, and impact of fatty liver disease in metastatic HR+/HER2− breast cancer patients treated with Endocrine Therapy and CDK 4/6 Inhibitor [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-04-09.

MiRNA-seq and mRNA-seq revealed the mechanism of fluoride-induced cauda epididymal injury

The widespread presence of fluoride in water, food, and the environment continues to exacerbate the impact of fluoride on the male reproductive health. However, as a critical component of the male reproductive system, the intrinsic mechanism of fluoride-induced cauda epididymis damage and the role of miRNAs in this process are still unclear. This study established a mouse fluorosis model and employed miRNA and mRNA sequencing; Evans blue staining, Oil Red O staining, TEM, immunofluorescence, western blotting, and other technologies to investigate the mechanism of miRNA in fluoride-induced cauda epididymal damage. The results showed that fluoride exposure increased the fluoride concentration in the hard tissue and cauda epididymis, altered the morphology and ultrastructure of the cauda epididymis, and reduced the motility rate, normal morphology rate, and hypo-osmotic swelling index of the sperm in the cauda epididymis. Furthermore, sequencing results revealed that fluoride exposure resulted in differential expression of 17 miRNAs and 4725 mRNAs, which were primarily enriched in the biological processes of tight junctions, inflammatory response, and lipid metabolism, with miR-742-3p, miR-141-5p, miR-878-3p, and miR-143-5p serving as key regulators. Further verification found that fluoride damaged tight junctions, raised oxidative stress, induced an inflammatory response, increased lipid synthesis, and reduced lipid decomposition and transport in the cauda epididymis. This study provided a theoretical basis for developing miRNA as potential diagnostic markers and therapeutic target drugs for this injury.

MiR-743b-3p promotes hepatic lipogenesis via branched-chain amino acids (BCAA) metabolism by targeting PPM1K in aged mice

BackgroundLipid metabolism disorders appear to play an important role in the ageing process, thus understanding the cellular and molecular mechanisms underlying the association of ageing with elevated vulnerability to lipid metabolism related diseases is crucial towards promoting quality of life in old age. MicroRNAs (miRNAs) have emerged as crucial regulators of lipid metabolism, and some miRNAs have key roles in ageing. MethodsIn this study, we investigated changes in liver lipid metabolism of ageing mice and the mechanisms of the altered expression of miRNAs in the ageing liver which contributes to the age-dependent increase in lipid synthesis. Here we found that miR-743b-3p was higher expressed in the liver tissues of ageing mice through the small RNA sequencing and bioinformatics analysis, and its target PPM1K was predicted and confirmed the target relationship of miR-743b-3p with PPM1K in the aged mouse liver tissues and the cultured senescent hepatocytes in vitro. Moreover, using the transfected miR-743b-3p mimics/inhibitors into the senescent hepatocyte AML12. ResultsWe found that miR-743b-3p inhibition reversed the hepatocyte senescence, and finally decreased the expression of genes involved in lipid synthesis(Chrebp, Fabp4, Acly and Pparγ) through increasing the target gene expression of PPM1K which regulated the expression of branched-chain amino acids (BCAA) metabolism-related genes (Bckdhα, Bckdk, Bcat2, Dbt). ConclusionsThese results identify that age-induced expression of miR-743b-3p inhibits its target PPM1K which induces BCAA metabolic disorder and regulates hepatocyte lipid accumulation during ageing.

New trends in microbial lipid-based biorefinery for fermentative bioenergy production from lignocellulosic biomass

Using oleaginous microbial lipid-based biorefinery from lignocellulosic biomass (LCB) to produce fermentative bioenergy (i.e., biodiesel) represents an innovative second-generation fuel production technology. These lipids are predominantly intracellular triglycerides that accumulate through the metabolism of sugars in fermentation following pretreatment and enzymatic hydrolysis of LCB. This review investigates the recent advances in the microbial lipid production from LCB, focusing on the factors influencing the lead microbial lipid producers, different pretreatment methods (i.e., physical, chemical, biological, and combined pretreatment), enzymatic hydrolysis approaches, novel bioprocessing strategies (i.e., microbes-specific and fermentation model specific), and engineering techniques of the oleaginous microbes (i.e., genetic and metabolic alterations). The study demonstrates that oleaginous yeasts can synthesize significantly higher quantities of lipids when incorporated into the system, known as separated hydrolysis and lipid production, following various combined pretreatment methods. Interestingly, CRISPR is found to be the most suitable way of engineering microbes genetically and metabolically for increased lipid synthesis. The study also explores economically viable strategies for fermentative lipid production, addressing associated challenges, and outlines future directions, including comprehensive techno-economic and life cycle assessments. This review offers invaluable insights into microbial lipid production from LCB, highlighting the potential for significant technological and environmental enhancements through ongoing research and development efforts.

Low phosphorus increases hepatic lipid deposition, oxidative stress and inflammatory response via Acetyl-CoA carboxylase-dependent manner in zebrafish liver cells

Acetyl-CoA carboxylase (ACC) plays a regulatory role in both fatty acid synthesis and oxidation, controlling the process of lipid deposition in the liver. Given that existing studies have shown a close relationship between low phosphorus (P) and hepatic lipid deposition, this study was conducted to investigate whether ACC plays a crucial role in this relationship. Zebrafish liver cell line (ZFL) was incubated under low P medium (LP, P concentration: 0.77 mg/L) or adequate P medium (AP, P concentration: 35 mg/L) for 240 h. The results showed that, compared with AP-treated cells, LP-treated cells displayed elevated lipid accumulation, and reduced fatty acid β-oxidation, ATP content, and mitochondrial mass. Furthermore, transcriptomics analysis revealed that LP-treated cells significantly increased lipid synthesis (Acetyl-CoA carboxylases (acc), Stearyl coenzyme A dehydrogenase (scd)) but decreased fatty acid β-oxidation (Carnitine palmitoyltransferase I (cptI)) and (AMP-activated protein kinase (ampk)) mRNA levels compared to AP-treated cells. The phosphorylation of AMPK and ACC, and the protein expression of CPTI were significantly decreased in LP-treated cells compared with those in AP-treated cells. After 240 h of LP treatment, PF-05175157 (an ACC inhibitor) was supplemented in the LP treatment for an additional 12 h. PF-05175157-treated cells showed higher phosphorylation of ACC, higher protein expression of CPTI, and lower protein expression of FASN, lower TG content, enhanced fatty acid β-oxidation, increased ATP content, and mitochondrial mass compared with LP-treated cells. PF-05175157 also relieved the LP-induced oxidative stress and inflammatory response. Overall, these findings suggest that ACC is a promising target for treating LP-induced elevation of lipid deposition in ZFL, and can alleviate oxidative stress and inflammatory response.

Involvement of tumor immune microenvironment metabolic reprogramming in colorectal cancer progression, immune escape, and response to immunotherapy.

Metabolic reprogramming is a k`ey hallmark of tumors, developed in response to hypoxia and nutrient deficiency during tumor progression. In both cancer and immune cells, there is a metabolic shift from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, also known as the Warburg effect, which then leads to lactate acidification, increased lipid synthesis, and glutaminolysis. This reprogramming facilitates tumor immune evasion and, within the tumor microenvironment (TME), cancer and immune cells collaborate to create a suppressive tumor immune microenvironment (TIME). The growing interest in the metabolic reprogramming of the TME, particularly its significance in colorectal cancer (CRC)-one of the most prevalent cancers-has prompted us to explore this topic. CRC exhibits abnormal glycolysis, glutaminolysis, and increased lipid synthesis. Acidosis in CRC cells hampers the activity of anti-tumor immune cells and inhibits the phagocytosis of tumor-associated macrophages (TAMs), while nutrient deficiency promotes the development of regulatory T cells (Tregs) and M2-like macrophages. In CRC cells, activation of G-protein coupled receptor 81 (GPR81) signaling leads to overexpression of programmed death-ligand 1 (PD-L1) and reduces the antigen presentation capability of dendritic cells. Moreover, the genetic and epigenetic cell phenotype, along with the microbiota, significantly influence CRC metabolic reprogramming. Activating RAS mutations and overexpression of epidermal growth factor receptor (EGFR) occur in approximately 50% and 80% of patients, respectively, stimulating glycolysis and increasing levels of hypoxia-inducible factor 1 alpha (HIF-1α) and MYC proteins. Certain bacteria produce short-chain fatty acids (SCFAs), which activate CD8+ cells and genes involved in antigen processing and presentation, while other mechanisms support pro-tumor activities. The use of immune checkpoint inhibitors (ICIs) in selected CRC patients has shown promise, and the combination of these with drugs that inhibit aerobic glycolysis is currently being intensively researched to enhance the efficacy of immunotherapy.

Comparative analysis of the liver transcriptome in the red-eared slider (Trachemys scripta elegans) post exposure to noise.

Exposure to noise can cause non-auditory health problems and has been widely studied in mammals such as rats and rabbits. However, the non-auditory effects of noise exposure on reptiles (such as red-eared sliders) remain unclear. In this study, we determined the noise exposure-induced transcriptomic changes in the liver of red-eared slider (Trachemys scripta elegans) using Illumina Novaseq6000 sequencing technology. The transcriptome analysis identified 176 differentially expressed genes (DEGs), which were mainly enriched in lipid metabolism. KEGG analysis showed that by affecting the peroxisome proliferator activated receptor (PPAR) signaling pathway these DEGs increased lipid synthesis and decreased lipid oxidation. The Oil Red O staining results validated our data that noise exposure increased hepatic lipid deposition. Thus, noise exposure may lead to lipid accumulation and toxicity, mitochondrial damage, and accelerated oxidative stress. Our findings provide insights into the molecular process underlying non-auditory damage caused by noise exposure in T. scripta elegans.

Zebrafish cobll1a regulates lipid homeostasis via the RA signaling pathway.

The COBLL1 gene has been implicated in human central obesity, fasting insulin levels, type 2 diabetes, and blood lipid profiles. However, its molecular mechanisms remain largely unexplored. In this study, we established cobll1a mutant lines using the CRISPR/Cas9-mediated gene knockout technique. To further dissect the molecular underpinnings of cobll1a during early development, transcriptome sequencing and bioinformatics analysis was employed. Our study showed that compared to the control, cobll1a -/- zebrafish embryos exhibited impaired development of digestive organs, including the liver, intestine, and pancreas, at 4 days post-fertilization (dpf). Transcriptome sequencing and bioinformatics analysis results showed that in cobll1a knockout group, the expression level of genes in the Retinoic Acid (RA) signaling pathway was affected, and the expression level of lipid metabolism-related genes (fasn, scd, elovl2, elovl6, dgat1a, srebf1 and srebf2) were significantly changed (p < 0.01), leading to increased lipid synthesis and decreased lipid catabolism. The expression level of apolipoprotein genes (apoa1a, apoa1b, apoa2, apoa4a, apoa4b, and apoea) genes were downregulated. Our study suggest that the loss of cobll1a resulted in disrupted RA metabolism, reduced lipoprotein expression, and abnormal lipid transport, therefore contributing to lipid accumulation and deleterious effects on early liver development.

Lipid metabolism, amino acid metabolism, and prostate cancer: a crucial metabolic journey.

Prostate cancer (PCa) is one of the most common malignancies in males worldwide, and its development and progression involve the regulation of multiple metabolic pathways. Alterations in lipid metabolism affect the proliferation and metastatic capabilities of PCa cells. Cancer cells increase lipid synthesis and regulate fatty acid oxidation to meet their growth and energy demands. Similarly, changes occur in amino acid metabolism in PCa. Cancer cells exhibit an increased demand for specific amino acids, and they regulate amino acid transport and metabolic pathways to fulfill their proliferation and survival requirements. These changes are closely associated with disease progression and treatment response in PCa cells. Therefore, a comprehensive investigation of the metabolic characteristics of PCa is expected to offer novel insights and approaches for the early diagnosis and treatment of this disease.

TREM2 regulates microglial lipid droplet formation and represses post-ischemic brain injury

Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane receptor protein predominantly expressed in microglia within the central nervous system (CNS). TREM2 regulates multiple microglial functions, including lipid metabolism, immune reaction, inflammation, and microglial phagocytosis. Recent studies have found that TREM2 is highly expressed in activated microglia after ischemic stroke. However, the role of TREM2 in the pathologic response after stroke remains unclear. Herein, TREM2-deficient microglia exhibit an impaired phagocytosis rate and cholesteryl ester (CE) accumulation, leading to lipid droplet formation and upregulation of Perilipin-2 (PLIN2) expression after hypoxia. Knockdown of TREM2 results in increased lipid synthesis (PLIN2, SOAT1) and decreased cholesterol clearance and lipid hydrolysis (LIPA, ApoE, ABCA1, NECH1, and NPC2), further impacting microglial phenotypes. In these lipid droplet-rich microglia, the TGF-β1/Smad2/3 signaling pathway is downregulated, driving microglia towards a pro-inflammatory phenotype. Meanwhile, in a neuron-microglia co-culture system under hypoxic conditions, we found that microglia lost their protective effect against neuronal injury and apoptosis when TREM2 was knocked down. Under in vivo conditions, TREM2 knockdown mice express lower TGF-β1 expression levels and a lower number of anti-inflammatory M2 phenotype microglia, resulting in increased cerebral infarct size, exacerbated neuronal apoptosis, and aggravated neuronal impairment. Our work suggests that TREM2 attenuates stroke-induced neuroinflammation by modulating the TGF-β1/Smad2/3 signaling pathway. TREM2 may play a direct role in the regulation of inflammation and also exert an influence on the post-ischemic inflammation and the stroke pathology progression via regulation of lipid metabolism processes. Thus, underscoring the therapeutic potential of TREM2 agonists in ischemic stroke and making TREM2 an attractive new clinical target for the treatment of ischemic stroke and other inflammation-related diseases.

Long non‑coding RNAs, lipid metabolism and cancer (Review).

Cancer has emerged as the most common cause of death in China. The change in lipid metabolism has been confirmed to have a role in several tumor types, such as esophageal, gastric, colorectal and liver cancer. Cancer cells use lipid metabolism for energy and then rapidly proliferate, invade and migrate. The main pathway by which cancer cell lipid metabolism influences cancer progression is increased fatty acid synthesis. Long non-coding (lnc)RNAs are important ncRNAs that were indicated to have significant roles in the development of human tumors. They are considered potential tumor biomarkers. Increased lipid synthesis or uptake due to deregulation of lncRNAs contributes to rapid tumor growth. In the present review, current studies on the relationship between lncRNAs, lipid metabolism and the occurrence and development of tumors were collated and summarized, and their mechanism of action was discussed. The review is expected to provide a theoretical basis for tumor treatment and prognosis evaluation based on the effective regulation of lncRNAs and lipid metabolism.

Antioxidant Peptides from Monkfish Swim Bladders: Ameliorating NAFLD In Vitro by Suppressing Lipid Accumulation and Oxidative Stress via Regulating AMPK/Nrf2 Pathway.

In this study, we investigate the ameliorating functions of QDYD (MSP2), ARW (MSP8), DDGGK (MSP10), YPAGP (MSP13) and DPAGP (MSP18) from monkfish swim bladders on an FFA-induced NAFLD model of HepG2 cells. The lipid-lowering mechanisms revealed that these five oligopeptides can up-regulate the expression of phospho-AMP-activated protein kinase (p-AMPK) proteins to inhibit the expression of the sterol regulatory element binding protein-1c (SREBP-1c) proteins on increasing lipid synthesis and up-regulating the expression of the PPAP-α and CPT-1 proteins on promoting the β-oxidation of fatty acids. Moreover, QDYD (MSP2), ARW (MSP8), DDGGK (MSP10), YPAGP (MSP13) and DPAGP (MSP18) can significantly inhibit reactive oxygen species' (ROS) production, promote the activities of intracellular antioxidases (superoxide dismutase, SOD; glutathione peroxidase, GSH-PX; and catalase, CAT) and bring down the content of malondialdehyde (MDA) derived from lipid peroxidation. Further investigations revealed that the regulation of these five oligopeptides on oxidative stress was achieved through activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway to raise the expression levels of the heme oxygenase 1 (HO-1) protein and downstream antioxidant proteases. Therefore, QDYD (MSP2), ARW (MSP8), DDGGK (MSP10), YPAGP (MSP13) and DPAGP (MSP18) could serve as candidate ingredients to develop functional products for treating NAFLD.

Indirect insulin resistance markers are associated with nonalcoholic fatty liver disease in type 1 diabetes.

Insulin resistance (IR) in type 1 diabetes mellitus (T1DM) is associated with increased insulin dose requirements, poor glycemic control, and elevated risk of chronic complications. IR increases lipid synthesis and hepatic lipid content. Disruption in hepatic lipid accumulation and export leads to liver steatosis resulting in nonalcoholic liver disease (NAFLD). The aim of the study was to explore the relationship between indirect IR markers and NAFLD in T1DM. We analyzed 151 patients with T1DM (59 men, 92 women), with a median (interquartile range [IQR]) age of 40 (33-47) years and a median (IQR) diabetes duration of 19 (13-21)years. The median (IQR) value of glycated hemoglobin (HbA1c) was 7.5% (6.8%-8.%; 58 [51-66] mmol/mol). The following indirect IR markers were evaluated: estimated glucose distribution rate (eGDR), visceral adiposity index (VAI), and the triglyceride to high‑density lipoprotein cholesterol ratio (TG/HDL‑C). Fatty infiltration of the liver was quantified using transient elastography. Presence of NAFLD was defined as a controlled attenuation parameter value of 238 dB/m or greater. NAFLD was observed in 65 patients (43%). The participants with NAFLD were less insulin‑sensitive (eGDR, 8.93 [6.39-9.97] vs 9.94 [8.09-11.13] mg/kg/min; P = 0.001; VAI, 1.52 [1.2-2.64] vs 1.34 [0.92-1.74]; P = 0.014; TG/HDL‑C ratio, 1.35 [0.95-2.11] vs 1.11 [0.77-1.6]; P = 0.02) and were characterized by higher HbA1c values (7.75% [7.2%-8.4%] vs 7.3% [6.5%-8.1%]; 61 [55-68] vs 56 [48-65] mmol/mol; P = 0.02) than the patients without the disease. In a multivariable regression analysis adjusted for sex, diabetes duration, and HbA1c level, indirect IR markers were independently associated with NAFLD (eGDR: odds ratio [OR], 0.86; 95% CI, 0.77-0.97; P = 0.01; VAI: OR, 1.61; 95% CI, 1.05-2.49; P = 0.03, TG/HDL‑C ratio: OR, 1.88; 95% CI, 1.11-3.18; P = 0.02). In T1DM, NAFLD is more likely to be found in individuals with lower insulin sensitivity.

Loss of Mature Lamin A/C Triggers a Shift in Intracellular Metabolic Homeostasis via AMPKα Activation

The roles of lamin A/C in adipocyte differentiation and skeletal muscle lipid metabolism are associated with familial partial lipodystrophy of Dunnigan (FPLD). We confirmed that LMNA knockdown (KD) in mouse adipose-derived mesenchymal stem cells (AD-MSCs) prevented adipocyte maturation. Importantly, in in vitro experiments, we discovered a significant increase in phosphorylated lamin A/C levels at serine 22 or 392 sites (pLamin A/C-S22/392) accompanying increased lipid synthesis in a liver cell line (7701 cells) and two hepatocellular carcinoma (HCC) cell lines (HepG2 and MHCC97-H cells). Moreover, HCC cells did not survive after LMNA knockout (KO) or even KD. Evidently, the functions of lamin A/C differ between the liver and adipose tissue. To date, the mechanism of hepatocyte lipid metabolism mediated by nuclear lamin A/C remains unclear. Our in-depth study aimed to identify the molecular connection between lamin A/C and pLamin A/C, hepatic lipid metabolism and liver cancer. Gain- and loss-of-function experiments were performed to investigate functional changes and the related molecular pathways in 7701 cells. Adenosine 5' monophosphate-activated protein kinase α (AMPKα) was activated when abnormalities in functional lamin A/C were observed following lamin A/C depletion or farnesyltransferase inhibitor (FTI) treatment. Active AMPKα directly phosphorylated acetyl-CoA-carboxylase 1 (ACC1) and subsequently inhibited lipid synthesis but induced glycolysis in both HCC cells and normal cells. According to the mass spectrometry analysis, lamin A/C potentially regulated AMPKα activation through its chaperone proteins, ATPase or ADP/ATP transporter 2. Lonafarnib (an FTI) combined with low-glucose conditions significantly decreased the proliferation of the two HCC cell lines more efficiently than lonafarnib alone by inhibiting glycolysis or the maturation of prelamin A.

Transcriptome Analysis of Particulate Matter 2.5-Induced Abnormal Effects on Human Sebocytes.

Particulate matter 2.5 (PM2.5), an atmospheric pollutant with an aerodynamic diameter of <2.5 μm, can cause serious human health problems, including skin damage. Since sebocytes are involved in the regulation of skin homeostasis, it is necessary to study the effects of PM2.5 on sebocytes. We examined the role of PM2.5 via the identification of differentially expressed genes, functional enrichment and canonical pathway analysis, upstream regulator analysis, and disease and biological function analysis through mRNA sequencing. Xenobiotic and lipid metabolism, inflammation, oxidative stress, and cell barrier damage-related pathways were enriched; additionally, PM2.5 altered steroid hormone biosynthesis and retinol metabolism-related pathways. Consequently, PM2.5 increased lipid synthesis, lipid peroxidation, inflammatory cytokine expression, and oxidative stress and altered the lipid composition and expression of factors that affect cell barriers. Furthermore, PM2.5 altered the activity of sterol regulatory element binding proteins, mitogen-activated protein kinases, transforming growth factor beta-SMAD, and forkhead box O3-mediated pathways. We also suggest that the alterations in retinol and estrogen metabolism by PM2.5 are related to the damage. These results were validated using the HairSkin® model. Thus, our results provide evidence of the harmful effects of PM2.5 on sebocytes as well as new targets for alleviating the skin damage it causes.

PACS-2 deficiency in tubular cells aggravates lipid-related kidney injury in diabetic kidney disease

BackgroundLipid accumulation in tubular cells plays a key role in diabetic kidney disease (DKD). Targeting lipid metabolism disorders has clinical value in delaying the progression of DKD, but the precise mechanism by which molecules mediate lipid-related kidney injury remains unclear. Phosphofurin acidic cluster sorting protein 2 (PACS-2) is a multifunctional sorting protein that plays a role in lipid metabolism. This study determined the role of PACS-2 in lipid-related kidney injury in DKD.MethodsDiabetes was induced by a high-fat diet combined with intraperitoneal injections of streptozotocin (HFD/STZ) in proximal tubule-specific knockout of Pacs-2 mice (PT-Pacs-2−/− mice) and the control mice (Pacs-2fl/fl mice). Transcriptomic analysis was performed between Pacs-2fl/fl mice and PT-Pacs-2−/− mice.ResultsDiabetic PT-Pacs-2−/− mice developed more severe tubule injury and proteinuria compared to diabetic Pacs-2fl/fl mice, which accompanied with increasing lipid synthesis, uptake and decreasing cholesterol efflux as well as lipid accumulation in tubules of the kidney. Furthermore, transcriptome analysis showed that the mRNA level of sterol O-acyltransferase 1 (Soat1) was up-regulated in the kidney of control PT-Pacs-2−/− mice. Transfection of HK2 cells with PACS-2 siRNA under high glucose plus palmitic acid (HGPA) condition aggravated lipid deposition and increased the expression of SOAT1 and sterol regulatory element-binding proteins (SREBPs), while the effect was blocked partially in that of co-transfection of SOAT1 siRNA.ConclusionsPACS-2 has a protective role against lipid-related kidney injury in DKD through SOAT1/SREBPs signaling.

Effects of copper exposure on lipid metabolism and SREBP pathway in the Chinese mitten crab Eriocheir sinensis

Copper (Cu) is not only a common metal pollutant in the aquatic environment but also an essential trace element for aquatic organisms such as the Chinese mitten crab (Eriocheir sinensis). Cu is known to regulate lipid metabolism yet exert toxic effects if ingested in excess. However, the molecular regulatory roles of Cu in the lipid metabolism of crabs remains unclear. Thus, this study investigated the potential regulatory mechanism of Cu onto lipid metabolism of E. sinensis following acute Cu exposure. Crabs were exposed to environmental concentration of Cu (50 μg/L) for 96 h, and the expression of sterol regulatory element binding protein (SREBP) was knocked down by RNA interference (RNAi) to test its effect on Cu exposure. The results showed that RNAi significantly attenuated the Cu exposure-induced increase in lipid synthesis and triglycerides (TG) hydrolysis, while significantly inhibited the Cu exposure-induced decrease in fatty acid β-oxidation, suggesting that SREBP is involved in Cu-induced lipid metabolism. Subsequent analyses of the transcriptome results further revealed potential responsive genes of SREBP that were linked to lipid metabolism and immune regulation. Moreover, Cu may affect lipid metabolism through the TOR-SREBP pathway in E. sinensis. This work provides a reference for exploring the effects of Cu on lipid metabolism disorders in crustaceans.