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1.
Int J Mol Sci ; 25(7)2024 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-38612519

RESUMO

Angiopoietin-like 3 (ANGPTL3) is a hepatokine acting as a negative regulator of lipoprotein lipase (LPL). Vupanorsen, an ANGPTL3 directed antisense oligonucleotide, showed an unexpected increase in liver fat content in humans. Here, we investigated the molecular mechanism linking ANGPTL3 silencing to hepatocyte fat accumulation. Human hepatocarcinoma Huh7 cells were treated with small interfering RNA (siRNA) directed to ANGPTL3, human recombinant ANGPTL3 (recANGPTL3), or their combination. Using Western blot, Oil Red-O, biochemical assays, and ELISA, we analyzed the expression of genes and proteins involved in lipid metabolism. Oil Red-O staining demonstrated that lipid content increased after 48 h of ANGPTL3 silencing (5.89 ± 0.33 fold), incubation with recANGPTL3 (4.08 ± 0.35 fold), or their combination (8.56 ± 0.18 fold), compared to untreated cells. This effect was also confirmed in Huh7-LX2 spheroids. A total of 48 h of ANGPTL3 silencing induced the expression of genes involved in the de novo lipogenesis, such as fatty acid synthase, stearoyl-CoA desaturase, ATP citrate lyase, and Acetyl-Coenzyme A Carboxylase 1 together with the proprotein convertase subtilisin/kexin 9 (PCSK9). Time-course experiments revealed that 6 h post transfection with ANGPTL3-siRNA, the cholesterol esterification by Acyl-coenzyme A cholesterol acyltransferase (ACAT) was reduced, as well as total cholesterol content, while an opposite effect was observed at 48 h. Under the same experimental conditions, no differences in secreted apoB and PCSK9 were observed. Since PCSK9 was altered by the treatment, we tested a possible co-regulation between the two genes. The effect of ANGPTL3-siRNA on the expression of genes involved in the de novo lipogenesis was not counteracted by gene silencing of PCSK9. In conclusion, our in vitro study suggests that ANGPTL3 silencing determines lipid accumulation in Huh7 cells by inducing the de novo lipogenesis independently from PCSK9.


Assuntos
Lipogênese , Pró-Proteína Convertase 9 , Humanos , Lipogênese/genética , Subtilisinas , Inativação Gênica , RNA Interferente Pequeno/genética , Colesterol , Angiopoietinas/genética , Coenzima A , Proteína 3 Semelhante a Angiopoietina
2.
Int J Mol Sci ; 25(7)2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38612853

RESUMO

While the involvement of thermosensitive transient receptor potential channels (TRPs) in dry eye disease (DED) has been known for years, their expression in the meibomian gland (MG) has never been investigated. This study aims to show their expression and involvement in the lipogenesis of the MG, providing a possible new drug target in the treatment of DED. Our RT-PCR, Western blot and immunofluorescence analysis showed the expression of TRPV1, TRPV3, TRPV4 and TRPM8 in the MG at the gene and the protein level. RT-PCR also showed gene expression of TRPV2 but not TRPA1. Calcium imaging and planar patch-clamping performed on an immortalized human meibomian gland epithelial cell line (hMGECs) demonstrated increasing whole-cell currents after the application of capsaicin (TRPV1) or icilin (TRPM8). Decreasing whole-cell currents could be registered after the application of AMG9810 (TRPV1) or AMTB (TRPM8). Oil red O staining on hMGECs showed an increase in lipid expression after TRPV1 activation and a decrease after TRPM8 activation. We conclude that thermo-TRPs are expressed at the gene and the protein level in MGs. Moreover, TRPV1 and TRPM8's functional expression and their contribution to their lipid expression could be demonstrated. Therefore, TRPs are potential drug targets and their clinical relevance in the therapy of meibomian gland dysfunction requires further investigation.


Assuntos
Disfunção da Glândula Tarsal , Glândulas Tarsais , Humanos , Lipogênese/genética , Western Blotting , Capsaicina/farmacologia
3.
J Anim Sci ; 1022024 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-38563227

RESUMO

The liver plays a critical role in metabolic activity and is the body's first immune barrier, and maintaining liver health is particularly important for poultry production. MicroRNAs (miRNAs) are involved in a wide range of biological activities due to their capacity as posttranscriptional regulatory elements. A growing body of research indicates that miR-21-5p plays a vital role as a modulator of liver metabolism in various species. However, the effect of miR-21-5p on the chicken liver is unclear. In the current study, we discovered that the fatty liver had high levels of miR-21-5p. Then the qPCR, Western blot, flow cytometry, enzyme-linked immunosorbent assay, dual-luciferase, and immunofluorescence assays were, respectively, used to determine the impact of miR-21-5p in the chicken liver, and it turned out that miR-21-5p enhanced lipogenesis, oxidative stress, and inflammatory responses, which ultimately induced hepatocyte apoptosis. Mechanically, we verified that miR-21-5p can directly target nuclear factor I B (NFIB) and kruppel-like factor 3 (KLF3). Furthermore, our experiments revealed that the suppression of NFIB promoted apoptosis and inflammation, and the KLF3 inhibitor accelerated lipogenesis and enhanced oxidative stress. Furthermore, the cotransfection results suggest that the PI3K/AKT pathway is also involved in the process of miRNA-21-5p-mediate liver metabolism regulation. In summary, our study demonstrated that miRNA-21-5p plays a role in hepatocyte lipogenesis, oxidative stress, inflammation, and apoptosis, via targeting NFIB and KLF3 to suppress the PI3K/AKT signal pathway in chicken.


miR-21-5p is a typical noncoding RNA that could inhibit messenger RNA expression by targeting the 3ʹ-untranslated region to participate in fatty liver-related disease formation and progression. We demonstrated that miRNA-21-5p plays a role in hepatocyte lipogenesis, oxidative stress, inflammation, and apoptosis, via targeting nuclear factor I B and kruppel-like factor 3 to suppress the PI3K/AKT signal pathway in chicken. This research established the regulatory network mechanisms of miR-21-5p in chicken hepatic lipogenesis and fatty liver syndrome.


Assuntos
MicroRNAs , Proteínas Proto-Oncogênicas c-akt , Animais , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fatores de Transcrição NFI/metabolismo , Galinhas/genética , Galinhas/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Lipogênese/genética , Transdução de Sinais , MicroRNAs/genética , MicroRNAs/metabolismo , Fígado/metabolismo , Apoptose , Inflamação/metabolismo , Inflamação/veterinária , Proliferação de Células
4.
Sci Rep ; 14(1): 7742, 2024 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-38565895

RESUMO

Evidence from genetic and epidemiological studies point to lipid metabolism defects in both the brain and periphery being at the core of Alzheimer's disease (AD) pathogenesis. Previously, we reported that central inhibition of the rate-limiting enzyme in monounsaturated fatty acid synthesis, stearoyl-CoA desaturase (SCD), improves brain structure and function in the 3xTg mouse model of AD (3xTg-AD). Here, we tested whether these beneficial central effects involve recovery of peripheral metabolic defects, such as fat accumulation and glucose and insulin handling. As early as 3 months of age, 3xTg-AD mice exhibited peripheral phenotypes including increased body weight and visceral and subcutaneous white adipose tissue as well as diabetic-like peripheral gluco-regulatory abnormalities. We found that intracerebral infusion of an SCD inhibitor that normalizes brain fatty acid desaturation, synapse loss and learning and memory deficits in middle-aged memory-impaired 3xTg-AD mice did not affect these peripheral phenotypes. This suggests that the beneficial effects of central SCD inhibition on cognitive function are not mediated by recovery of peripheral metabolic abnormalities. Given the widespread side-effects of systemically administered SCD inhibitors, these data suggest that selective inhibition of SCD in the brain may represent a clinically safer and more effective strategy for AD.


Assuntos
Doença de Alzheimer , Estearoil-CoA Dessaturase , Camundongos , Animais , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Metabolismo dos Lipídeos/fisiologia , Lipogênese , Modelos Animais de Doenças , Camundongos Transgênicos
5.
Zool Res ; 45(2): 355-366, 2024 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-38485505

RESUMO

Testosterone is closely associated with lipid metabolism and known to affect body fat composition and muscle mass in males. However, the mechanisms by which testosterone acts on lipid metabolism are not yet fully understood, especially in teleosts. In this study, cyp17a1-/- zebrafish ( Danio rerio) exhibited excessive visceral adipose tissue (VAT), lipid content, and up-regulated expression and activity of hepatic de novo lipogenesis (DNL) enzymes. The assay for transposase accessible chromatin with sequencing (ATAC-seq) results demonstrated that chromatin accessibility of DNL genes was increased in cyp17a1-/- fish compared to cyp17a1+/+ male fish, including stearoyl-CoA desaturase ( scd) and fatty acid synthase ( fasn). Androgen response element (ARE) motifs in the androgen signaling pathway were significantly enriched in cyp17a1+/+ male fish but not in cyp17a1-/- fish. Both androgen receptor ( ar)-/- and wild-type (WT) zebrafish administered with Ar antagonist flutamide displayed excessive visceral adipose tissue, lipid content, and up-regulated expression and activity of hepatic de novo lipogenesis enzymes. The Ar agonist BMS-564929 reduced the content of VAT and lipid content, and down-regulated acetyl-CoA carboxylase a ( acaca), fasn, and scd expression. Mechanistically, the rescue effect of testosterone on cyp17a1-/- fish in terms of phenotypes was abolished when ar was additionally depleted. Collectively, these findings reveal that testosterone inhibits lipid deposition by down-regulating DNL genes via Ar in zebrafish, thus expanding our understanding of the relationship between testosterone and lipid metabolism in teleosts.


Assuntos
Androgênios , Lipogênese , Masculino , Animais , Androgênios/farmacologia , Lipogênese/genética , Peixe-Zebra/genética , Testosterona , Lipídeos , Transdução de Sinais , Cromatina
6.
Arch Insect Biochem Physiol ; 115(3): e22098, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38500442

RESUMO

In the current study, we investigated the insecticidal efficacy of two borates, disodium octaborate tetrahydrate (Etidot-67) and calcium metaborate (CMB) via surface application or diet delivery on the red flour beetle, Tribolium castaneum (Herbst, 1797) (Coleoptera: Tenebrionidae). The application method did not change the boron-related mortality, but CMB was more effective than Etidot-67. At the highest dose, it took around 13 days to reach the highest mortality (≥98.1%) for CMB, while it was 19 days for Etidot-67 (≥95.8%). Both boron compounds led to a significant reduction in triglyceride levels in parallel to the downregulation of acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), the two primary genes involved in de novo lipogenesis, while they also induced body weight loss. In conclusion, the current study indicated the insecticidal potential of boron compounds but CMB is more promising and more effective in controlling T. castaneum, while lipogenesis is inhibited and weight loss is induced by boron compounds.


Assuntos
Besouros , Inseticidas , Tribolium , Animais , Lipogênese , Inseticidas/farmacologia , Compostos de Boro , Cálcio
7.
Exp Eye Res ; 241: 109851, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38453039

RESUMO

The accumulation of oleic acid (OA) in the meibum from patients with meibomian gland dysfunction (MGD) suggests that it may contribute to meibomian gland (MG) functional disorder, as it is a potent stimulator of acne-related lipogenesis and inflammation in sebaceous gland. Therefore, we investigate whether OA induces lipogenesis and inflammasome activation in organotypic cultured mouse MG and human meibomian gland epithelial cells (HMGECs). Organotypic cultured mouse MG and HMGECs were exposed to OA or combinations with specific AMPK agonists 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR). Lipogenic status, ductal keratinization, squamous metaplasia, NLRP3/ASC/Caspase-1 inflammasome activation, proinflammatory cytokine IL-1ß production, and AMPK pathway phosphorylation in MG were subsequently examined by lipid staining, immunofluorescence staining, immunohistochemical staining, ELISA assay, and Western blot analyses. We found that OA significantly induced lipid accumulation, ductal keratinization, and squamous metaplasia in organotypic cultured MG, as evidenced by increased lipids deposition within acini and duct, upregulated expression of lipogenic proteins (SREBP-1 and HMGCR), and elevation of K10/Sprr1b. Additionally, OA induced NLRP3/ASC/Caspase-1 inflammasome activation, cleavage of Caspase-1, and production of downstream proinflammatory cytokine IL-1ß. The findings of lipogenesis and NLRP3-related proinflammatory response in OA-stimulated HMGECs were consistent with those in organotypic cultured MG. OA exposure downregulated phospho-AMPK in two models, while AICAR treatment alleviated lipogenesis by improving AMPK/ACC phosphorylation and SREBP-1/HMGCR expression. Furthermore, AMPK amelioration inhibited activation of the NLRP3/ASC/Caspase-1 axis and secretion of IL-1ß, thereby relieving the OA-induced proinflammatory response. These results demonstrated that OA induced lipogenic disorder and NLRP3 inflammasome activation in organotypic cultured mouse MG and HMGECs by suppressing the AMPK signaling pathway, indicating OA may play an etiological role in MGD.


Assuntos
Carcinoma de Células Escamosas , Inflamassomos , Humanos , Camundongos , Animais , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Ácido Oleico/farmacologia , Ácido Oleico/metabolismo , Glândulas Tarsais/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Lipogênese , Células Epiteliais/metabolismo , Caspase 1/metabolismo , Citocinas/metabolismo , Metaplasia/metabolismo , Carcinoma de Células Escamosas/metabolismo , Interleucina-1beta/metabolismo
8.
J Histochem Cytochem ; 72(4): 245-264, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38544368

RESUMO

Liver regeneration is a well-orchestrated compensatory process that is regulated by multiple factors. We recently reported the importance of the chromatin protein, a high-mobility group box 2 (HMGB2) in mouse liver regeneration. However, the molecular mechanism remains unclear. In this study, we aimed to study how HMGB2 regulates hepatocyte proliferation during liver regeneration. Seventy-percent partial hepatectomy (PHx) was performed in wild-type (WT) and HMGB2-knockout (KO) mice, and the liver tissues were used for microarray, immunohistochemistry, quantitative polymerase chain reaction (qPCR), and Western blotting analyses. In the WT mice, HMGB2-positive hepatocytes colocalized with cell proliferation markers. In the HMGB2-KO mice, hepatocyte proliferation was significantly decreased. Oil Red O staining revealed the transient accumulation of lipid droplets at 12-24 hr after PHx in the WT mouse livers. In contrast, decreased amount of lipid droplets were found in HMGB2-KO mouse livers, and it was preserved until 36 hr. The microarray, immunohistochemistry, and qPCR results demonstrated that the expression of lipid metabolism-related genes was significantly decreased in the HMGB2-KO mouse livers. The in vitro experiments demonstrated that a decrease in the amount of lipid droplets correlated with decreased cell proliferation activity in HMGB2-knockdown cells. HMGB2 promotes de novo lipogenesis to accelerate hepatocyte proliferation during liver regeneration.


Assuntos
Proteína HMGB2 , Regeneração Hepática , Camundongos , Animais , Regeneração Hepática/genética , Proteína HMGB2/genética , Proteína HMGB2/metabolismo , Lipogênese , Fígado/metabolismo , Proliferação de Células , Hepatócitos , Camundongos Knockout , Fatores de Transcrição/metabolismo , Camundongos Endogâmicos C57BL
9.
Acta Biochim Biophys Sin (Shanghai) ; 56(4): 621-633, 2024 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-38516704

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, with a global prevalence of 25%. Patients with NAFLD are more likely to suffer from advanced liver disease, cardiovascular disease, or type II diabetes. However, unfortunately, there is still a shortage of FDA-approved therapeutic agents for NAFLD. Lian-Mei-Yin (LMY) is a traditional Chinese medicine formula used for decades to treat liver disorders. It has recently been applied to type II diabetes which is closely related to insulin resistance. Given that NAFLD is another disease involved in insulin resistance, we hypothesize that LMY might be a promising formula for NAFLD therapy. Herein, we verify that the LMY formula effectively reduces hepatic steatosis in diet-induced zebrafish and NAFLD model mice in a time- and dose-dependent manner. Mechanistically, LMY suppresses Yap1-mediated Foxm1 activation, which is crucial for the occurrence and development of NAFLD. Consequently, lipogenesis is ameliorated by LMY administration. In summary, the LMY formula alleviates diet-induced NAFLD in zebrafish and mice by inhibiting Yap1/Foxm1 signaling-mediated NAFLD pathology.


Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica , Humanos , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Lipogênese , Peixe-Zebra , Diabetes Mellitus Tipo 2/metabolismo , Fígado/metabolismo , Dieta Hiperlipídica , Fatores de Transcrição/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Lipídeos , Camundongos Endogâmicos C57BL , Proteína Forkhead Box M1/metabolismo
11.
Science ; 383(6690): 1484-1492, 2024 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-38547260

RESUMO

Cellular purines, particularly adenosine 5'-triphosphate (ATP), fuel many metabolic reactions, but less is known about the direct effects of pyrimidines on cellular metabolism. We found that pyrimidines, but not purines, maintain pyruvate oxidation and the tricarboxylic citric acid (TCA) cycle by regulating pyruvate dehydrogenase (PDH) activity. PDH activity requires sufficient substrates and cofactors, including thiamine pyrophosphate (TPP). Depletion of cellular pyrimidines decreased TPP synthesis, a reaction carried out by TPP kinase 1 (TPK1), which reportedly uses ATP to phosphorylate thiamine (vitamin B1). We found that uridine 5'-triphosphate (UTP) acts as the preferred substrate for TPK1, enabling cellular TPP synthesis, PDH activity, TCA-cycle activity, lipogenesis, and adipocyte differentiation. Thus, UTP is required for vitamin B1 utilization to maintain pyruvate oxidation and lipogenesis.


Assuntos
Ciclo do Ácido Cítrico , Lipogênese , Pirimidinas , Complexo Piruvato Desidrogenase , Piruvatos , Trifosfato de Adenosina/metabolismo , Pirimidinas/metabolismo , Piruvatos/metabolismo , Tiamina/metabolismo , Tiamina Pirofosfato/metabolismo , Uridina Trifosfato/metabolismo , Oxirredução , Proteínas Quinases/metabolismo , Humanos , Células HeLa , Complexo Piruvato Desidrogenase/metabolismo
12.
Mol Metab ; 82: 101913, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38458567

RESUMO

OBJECTIVE: Adipose tissue mass is maintained by a balance between lipolysis and lipid storage. The contribution of adipose tissue lipogenesis to fat mass, especially in the setting of high-fat feeding, is considered minor. Here we investigated the effect of adipose-specific inactivation of the peroxisomal lipid synthetic protein PexRAP on fatty acid synthase (FASN)-mediated lipogenesis and its impact on adiposity and metabolic homeostasis. METHODS: To explore the role of PexRAP in adipose tissue, we metabolically phenotyped mice with adipose-specific knockout of PexRAP. Bulk RNA sequencing was used to determine transcriptomic responses to PexRAP deletion and 14C-malonyl CoA allowed us to measure de novo lipogenic activity in adipose tissue of these mice. In vitro cell culture models were used to elucidate the mechanism of cellular responses to PexRAP deletion. RESULTS: Adipose-specific PexRAP deletion promoted diet-induced obesity and insulin resistance through activation of de novo lipogenesis. Mechanistically, PexRAP inactivation inhibited the flux of carbons to ethanolamine plasmalogens. This increased the nuclear PC/PE ratio and promoted cholesterol mislocalization, resulting in activation of liver X receptor (LXR), a nuclear receptor known to be activated by increased intracellular cholesterol. LXR activation led to increased expression of the phospholipid remodeling enzyme LPCAT3 and induced FASN-mediated lipogenesis, which promoted diet-induced obesity and insulin resistance. CONCLUSIONS: These studies reveal an unexpected role for peroxisome-derived lipids in regulating LXR-dependent lipogenesis and suggest that activation of lipogenesis, combined with dietary lipid overload, exacerbates obesity and metabolic dysregulation.


Assuntos
Resistência à Insulina , Lipogênese , Animais , Camundongos , 1-Acilglicerofosfocolina O-Aciltransferase/metabolismo , Tecido Adiposo/metabolismo , Colesterol/metabolismo , Gorduras na Dieta/metabolismo , Lipogênese/genética , Receptores X do Fígado/metabolismo , Camundongos Knockout , Obesidade/metabolismo
13.
Cell Rep Med ; 5(3): 101477, 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38508143

RESUMO

Metabolic (dysfunction)-associated steatohepatitis (MASH) is the advanced stage of metabolic (dysfunction)-associated fatty liver disease (MAFLD) lacking approved clinical drugs. Adenosine A1 receptor (A1R), belonging to the G-protein-coupled receptors (GPCRs) superfamily, is mainly distributed in the central nervous system and major peripheral organs with wide-ranging physiological functions; however, the exact role of hepatic A1R in MAFLD remains unclear. Here, we report that liver-specific depletion of A1R aggravates while overexpression attenuates diet-induced metabolic-associated fatty liver (MAFL)/MASH in mice. Mechanistically, activation of hepatic A1R promotes the competitive binding of sterol-regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) to sequestosome 1 (SQSTM1), rather than protein kinase A (PKA) leading to SCAP degradation in lysosomes. Reduced SCAP hinders SREBP1c/2 maturation and thus suppresses de novo lipogenesis and inflammation. Higher hepatic A1R expression is observed in patients with MAFL/MASH and high-fat diet (HFD)-fed mice, which is supposed to be a physiologically adaptive response because A1R agonists attenuate MAFL/MASH in an A1R-dependent manner. These results highlight that hepatic A1R is a potential target for MAFL/MASH therapy.


Assuntos
Fígado Gorduroso , Receptor A1 de Adenosina , Humanos , Camundongos , Animais , Receptor A1 de Adenosina/genética , Receptor A1 de Adenosina/metabolismo , Fígado Gorduroso/tratamento farmacológico , Lipogênese/genética , Dieta Hiperlipídica/efeitos adversos
14.
J Transl Med ; 22(1): 290, 2024 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-38500157

RESUMO

Lipid metabolism is widely reprogrammed in tumor cells. Lipid droplet is a common organelle existing in most mammal cells, and its complex and dynamic functions in maintaining redox and metabolic balance, regulating endoplasmic reticulum stress, modulating chemoresistance, and providing essential biomolecules and ATP have been well established in tumor cells. The balance between lipid droplet formation and catabolism is critical to maintaining energy metabolism in tumor cells, while the process of energy metabolism affects various functions essential for tumor growth. The imbalance of synthesis and catabolism of fatty acids in tumor cells leads to the alteration of lipid droplet content in tumor cells. Diacylglycerol acyltransferase 1 and diacylglycerol acyltransferase 2, the enzymes that catalyze the final step of triglyceride synthesis, participate in the formation of lipid droplets in tumor cells and in the regulation of cell proliferation, migration and invasion, chemoresistance, and prognosis in tumor. Several diacylglycerol acyltransferase 1 and diacylglycerol acyltransferase 2 inhibitors have been developed over the past decade and have shown anti-tumor effects in preclinical tumor models and improvement of metabolism in clinical trials. In this review, we highlight key features of fatty acid metabolism and different paradigms of diacylglycerol acyltransferase 1 and diacylglycerol acyltransferase 2 activities on cell proliferation, migration, chemoresistance, and prognosis in tumor, with the hope that these scientific findings will have potential clinical implications.


Assuntos
Diacilglicerol O-Aciltransferase , Neoplasias , Animais , Humanos , Diacilglicerol O-Aciltransferase/genética , Diacilglicerol O-Aciltransferase/metabolismo , Triglicerídeos/metabolismo , Metabolismo dos Lipídeos , Lipogênese , Proliferação de Células , Mamíferos/metabolismo
15.
Int J Mol Sci ; 25(5)2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38474208

RESUMO

Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a prevalent clinical condition associated with elevated morbidity and mortality rates. Patients with MASLD treated with semaglutide, a glucagon-like peptide-1 receptor agonist, demonstrate improvement in terms of liver damage. However, the mechanisms underlaying this beneficial effect are not yet fully elucidated. We investigated the efficacy of semaglutide in halting MASLD progression using a genetic mouse model of diabesity. Leptin-receptor-deficient mice with obesity and diabetes (BKS db/db) were either untreated or administered with semaglutide for 11 weeks. Changes in food and water intake, body weight and glycemia were monitored throughout the study. Body fat composition was assessed by dual-energy X-ray absorptiometry. Upon sacrifice, serum biochemical parameters, liver morphology, lipidomic profile and liver-lipid-related pathways were evaluated. The semaglutide-treated mice exhibited lower levels of glycemia, body weight, serum markers of liver dysfunction and total and percentage of fat mass compared to untreated db/db mice without a significant reduction in food intake. Histologically, semaglutide reduced hepatic steatosis, hepatocellular ballooning and intrahepatic triglycerides. Furthermore, the treatment ameliorated the hepatic expression of de novo lipogenesis markers and modified lipid composition by increasing the amount of polyunsaturated fatty acids. The administration of semaglutide to leptin-receptor-deficient, hyperphagic and diabetic mice resulted in the amelioration of MASLD, likely independently of daily caloric intake, suggesting a direct effect of semaglutide on the liver through modulation of the lipid profile.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Fígado Gorduroso , Peptídeos Semelhantes ao Glucagon , Hepatopatia Gordurosa não Alcoólica , Humanos , Animais , Camundongos , Lipogênese , Leptina/metabolismo , Diabetes Mellitus Experimental/metabolismo , Fígado Gorduroso/metabolismo , Obesidade/metabolismo , Fígado/metabolismo , Peso Corporal , Triglicerídeos/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Camundongos Obesos
16.
J Clin Invest ; 134(4)2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38357930

RESUMO

Ten percent of the population worldwide suffers from chronic kidney disease (CKD), but the mechanisms driving CKD pathology are incompletely understood. While dysregulated lipid metabolism is one hallmark of CKD, the pathogenesis of cellular lipid accumulation remains unclear. In this issue of the JCI, Mukhi et al. Identify acyl-CoA synthetase short-chain family 2 (ACSS2) as a disease risk gene and demonstrate a role for ACSS2 in de novo lipogenesis (DNL). Notably, genetic or pharmacological inhibition of DNL protected against kidney disease progression in mice. These findings warrant evaluation of DNL inhibition with respect to efficacy and safety in people with CKD.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Insuficiência Renal Crônica , Humanos , Animais , Camundongos , Lipogênese/fisiologia , Insuficiência Renal Crônica/metabolismo , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo
17.
Sci Rep ; 14(1): 3547, 2024 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-38347122

RESUMO

Cholesterol deposition in intimal macrophages leads to foam cell formation and atherosclerosis. Reverse cholesterol transport (RCT), initiated by efflux of excess cholesterol from foam cells, counteracts atherosclerosis. However, targeting RCT by enhancing cholesterol efflux was so far accompanied by adverse hepatic lipogenesis. Here, we aimed to identify novel natural enhancers of macrophage cholesterol efflux suitable for the prevention of atherosclerosis. Plant extracts of an open-access library were screened for their capacity to increase cholesterol efflux in RAW264.7 macrophages trace-labeled with fluorescent BODIPY-cholesterol. Incremental functional validation of hits yielded two final extracts, elder (Sambucus nigra) and bitter orange (Citrus aurantium L.) that induced ATP binding cassette transporter A1 (ABCA1) expression and reduced cholesteryl ester accumulation in aggregated LDL-induced foam cells. Aqueous elder extracts were subsequently prepared in-house and both, flower and leaf extracts increased ABCA1 mRNA and protein expression in human THP-1 macrophages, while lipogenic gene expression in hepatocyte-derived cells was not induced. Chlorogenic acid isomers and the quercetin glycoside rutin were identified as the main polyphenols in elder extracts with putative biological action. In summary, elder flower and leaf extracts increase macrophage ABCA1 expression and reduce foam cell formation without adversely affecting hepatic lipogenesis.


Assuntos
Aterosclerose , Extratos Vegetais , Sambucus nigra , Sambucus , Humanos , Células Espumosas/metabolismo , Lipoproteínas LDL/metabolismo , Lipogênese , Colesterol/metabolismo , Aterosclerose/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo
18.
Proc Natl Acad Sci U S A ; 121(7): e2318024121, 2024 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-38330014

RESUMO

Lipid synthesis is regulated by the actions of Scap, a polytopic membrane protein that binds cholesterol in membranes of the endoplasmic reticulum (ER). When ER cholesterol levels are low, Scap activates SREBPs, transcription factors that upregulate genes for synthesis of cholesterol, fatty acids, and triglycerides. When ER cholesterol levels rise, the sterol binds to Scap, triggering conformational changes that prevent activation of SREBPs and halting synthesis of lipids. To achieve a molecular understanding of how cholesterol regulates the Scap/SREBP machine and to identify therapeutics for dysregulated lipid metabolism, cholesterol-mimetic compounds that specifically bind and inhibit Scap are needed. To accomplish this goal, we focused on Anthrolysin O (ALO), a pore-forming bacterial toxin that binds cholesterol with a specificity and sensitivity that is uncannily similar to Scap. We reasoned that a small molecule that would bind and inhibit ALO might also inhibit Scap. High-throughput screening of a ~300,000-compound library for ALO-binding unearthed one molecule, termed UT-59, which binds to Scap's cholesterol-binding site. Upon binding, UT-59 triggers the same conformation changes in Scap as those induced by cholesterol and blocks activation of SREBPs and lipogenesis in cultured cells. UT-59 also inhibits SREBP activation in the mouse liver. Unlike five previously reported inhibitors of SREBP activation, UT-59 is the only one that acts specifically by binding to Scap's cholesterol-binding site. Our approach to identify specific Scap inhibitors such as UT-59 holds great promise in developing therapeutic leads for human diseases stemming from elevated SREBP activation, such as fatty liver and certain cancers.


Assuntos
Toxinas Bacterianas , Lipogênese , Animais , Camundongos , Humanos , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Colesterol/metabolismo , Toxinas Bacterianas/metabolismo
19.
Mol Med ; 30(1): 28, 2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38383297

RESUMO

BACKGROUND: Lung cancer is the leading cause of cancer-related death worldwide. The sex differences in the occurrence and fatality rates of non-small cell lung cancer (NSCLC), along with its association with estrogen dependence, suggest that estrogen receptors (ERs) contribute to the development of NSCLC. However, the influence of G protein-coupled estrogen receptor (GPER1) on NSCLC remains to be determined. Escape from ferroptosis is one of the hallmarks of tumor discovered in recent years. In this context, the present study evaluated whether GPER1 promotes NSCLC progression by preventing ferroptosis, and the underlying mechanism through which GPER1 protects against ferroptosis was also explored. METHODS: The effects of GPER1 on the cytotoxicity of H2O2, the ferroptosis inducer RSL3, and Erastin were assessed using the CCK8 assay and plate cloning. Lipid peroxidation levels were measured based on the levels of MDA and BODIPY™581/591C11. GPER1 overexpression and knockdown were performed and G1 was used, and the expression of SCD1 and PI3K/AKT/mTOR signaling factors was measured. Immunofluorescence analysis and immunohistochemistry were performed on paired specimens to measure the correlation between the expression of GPER1 and SCD1 in NSCLC tissues. The effect of GPER1 on the cytotoxicity of cisplatin was measured in vitro using the CCK8 assay and in vivo using xenograft tumor models. RESULTS: GPER1 and G1 alleviated the cytotoxicity of H2O2, reduced sensitivity to RSL3, and impaired lipid peroxidation in NSCLC tissues. In addition, GPER1 and G1 promoted the protein and mRNA expression of SCD1 and the activation of PI3K/AKT/mTOR signaling. GPER1 and SCD1 expression were elevated and positively correlated in NSCLC tissues, and high GPER1 expression predicted a poor prognosis. GPER1 knockdown enhanced the antitumor activity of cisplatin in vitro and in vivo. CONCLUSION: GPER1 prevents ferroptosis in NSCLC by promoting the activation of PI3K/AKT/mTOR signaling, thereby inducing SCD1 expression. Therefore, treatments targeting GPER1 combined with cisplatin would exhibit better antitumor effects.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Ferroptose , Neoplasias Pulmonares , Humanos , Feminino , Masculino , Carcinoma Pulmonar de Células não Pequenas/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Pulmonares/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Cisplatino/farmacologia , Lipogênese , Peróxido de Hidrogênio/farmacologia , Peróxido de Hidrogênio/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Estrogênios , Receptores de Estrogênio/metabolismo , Proteínas de Ligação ao GTP , Estearoil-CoA Dessaturase/metabolismo
20.
Science ; 383(6684): eadi3332, 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38359126

RESUMO

The identification of mechanisms to store glucose carbon in the form of glycogen rather than fat in hepatocytes has important implications for the prevention of nonalcoholic fatty liver disease (NAFLD) and other chronic metabolic diseases. In this work, we show that glycogenesis uses its intermediate metabolite uridine diphosphate glucose (UDPG) to antagonize lipogenesis, thus steering both mouse and human hepatocytes toward storing glucose carbon as glycogen. The underlying mechanism involves transport of UDPG to the Golgi apparatus, where it binds to site-1 protease (S1P) and inhibits S1P-mediated cleavage of sterol regulatory element-binding proteins (SREBPs), thereby inhibiting lipogenesis in hepatocytes. Consistent with this mechanism, UDPG administration is effective at treating NAFLD in a mouse model and human organoids. These findings indicate a potential opportunity to ameliorate disordered fat metabolism in the liver.


Assuntos
Lipogênese , Glicogênio Hepático , Fígado , Hepatopatia Gordurosa não Alcoólica , Pró-Proteína Convertases , Serina Endopeptidases , Uridina Difosfato Glucose , Animais , Humanos , Camundongos , Carbono/metabolismo , Glucose/metabolismo , Hepatócitos/metabolismo , Fígado/metabolismo , Glicogênio Hepático/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Pró-Proteína Convertases/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Uridina Difosfato Glucose/administração & dosagem , Uridina Difosfato Glucose/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Células HEK293
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