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Metabolic dysfunction-associated steatotic liver disease (MASLD) originates from a homeostatic imbalance in hepatic lipid metabolism. Increased fat deposition in the liver of people suffering from MASLD predisposes them to develop further metabolic derangements, including diabetes mellitus, metabolic dysfunction-associated steatohepatitis (MASH), and other end-stage liver diseases. Unfortunately, only limited pharmacological therapies exist for MASLD to date. Autophagy, a cellular catabolic process, has emerged as a primary mechanism of lipid metabolism in mammalian hepatocytes. Furthermore, preclinical studies with autophagy modulators have shown promising results in resolving MASLD and mitigating its progress into deleterious liver pathologies. In this review, we discuss our current understanding of autophagy-mediated hepatic lipid metabolism, its therapeutic modulation for MASLD treatment, and current limitations and scope for clinical translation.
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Breast cancer is a heterogeneous disease, with a subpopulation of tumor cells known as breast cancer stem cells (BCSCs) with self-renewal and differentiation abilities that play a critical role in tumor initiation, progression, and therapy resistance. The tumor microenvironment (TME) is a complex area where diverse cancer cells reside creating a highly interactive environment with secreted factors, and the extracellular matrix. Autophagy, a cellular self-digestion process, influences dynamic cellular processes in the tumor TME integrating diverse signals that regulate tumor development and heterogeneity. Autophagy acts as a double-edged sword in the breast TME, with both tumor-promoting and tumor-suppressing roles. Autophagy promotes breast tumorigenesis by regulating tumor cell survival, migration and invasion, metabolic reprogramming, and epithelial-mesenchymal transition (EMT). BCSCs harness autophagy to maintain stemness properties, evade immune surveillance, and resist therapeutic interventions. Conversely, excessive, or dysregulated autophagy may lead to BCSC differentiation or cell death, offering a potential avenue for therapeutic exploration. The molecular mechanisms that regulate autophagy in BCSCs including the mammalian target of rapamycin (mTOR), AMPK, and Beclin-1 signaling pathways may be potential targets for pharmacological intervention in breast cancer. This review provides a comprehensive overview of the relationship between autophagy and BCSCs, highlighting recent advancements in our understanding of their interplay. We also discuss the current state of autophagy-targeting agents and their preclinical and clinical development in BCSCs.
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"Metabolic aging" refers to the gradual decline in cellular metabolic function across various tissues due to defective hormonal signaling, impaired nutrient sensing, mitochondrial dysfunction, replicative stress, and cellular senescence. While this process usually corresponds with chronological aging, the recent increase in metabolic diseases and cancers occurring at younger ages in humans suggests the premature onset of cellular fatigue and metabolic aging. Autophagy, a cellular housekeeping process facilitated by lysosomes, plays a crucial role in maintaining tissue rejuvenation and health. However, various environmental toxins, hormones, lifestyle changes, and nutrient imbalances can disrupt autophagy in humans. In this review, we explore the connection between autophagy and cellular metabolism, its regulation by extrinsic factors and its modulation to prevent the early onset of metabolic aging.
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Envelhecimento , Autofagia , Senescência Celular , Humanos , Envelhecimento/metabolismo , Animais , Lisossomos/metabolismo , Mitocôndrias/metabolismo , Transdução de SinaisRESUMO
BACKGROUND: Bone marrow mesenchymal stem cells (BM-MSC) are an integral part of the BM niche that is essential to maintain hematopoietic homeostasis. In aplastic anemia (AA), a few studies have reported phenotypic defects in the BM-MSC, such as reduced proliferation, imbalanced differentiation, and apoptosis; however, the alterations at the molecular level need to be better characterized. Therefore, the current study aims to identify the causative factors underlying the compromised functions of AA BM-MSC that might eventually be contributing to the AA pathobiology. METHODS: We performed RNA sequencing (RNA-Seq) using the Illumina platform to comprehend the distinction between the transcriptional landscape of AA and control BM-MSC. Further, we validated the alterations observed in senescence by Senescence- associated beta-galactosidase (SA -ß-gal) assay, DNA damage by γH2AX staining, and telomere attrition by relative telomere length assessment and telomerase activity assay. We used qRT-PCR to analyze changes in some of the genes associated with these molecular mechanisms. RESULTS: The transcriptome profiling revealed enrichment of senescence-associated genes and pathways in AA BM-MSC. The senescent phenotype of AA BM-MSC was accompanied by enhanced SA -ß-gal activity and elevated expression of senescence associated genes TP53, PARP1, and CDKN1A. Further, we observed increased γH2AX foci indicating DNA damage, reduced telomere length, and diminished telomerase activity in the AA BM-MSC. CONCLUSION: Our results highlight that AA BM-MSC have a senescent phenotype accompanied by other cellular defects like DNA damage and telomere attrition, which are most likely driving the senescent phenotype of AA BM-MSC thus hampering their hematopoiesis supporting properties as observed in AA.
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Anemia Aplástica , Células-Tronco Mesenquimais , Telomerase , Humanos , Anemia Aplástica/genética , Anemia Aplástica/metabolismo , Telomerase/genética , Telomerase/metabolismo , Células-Tronco Mesenquimais/metabolismo , Telômero/genética , Reparo do DNARESUMO
Non-alcoholic steatohepatitis (NASH) is a clinically serious stage of non-alcoholic fatty liver disease (NAFLD). Histologically characterized by hepatocyte ballooning, immune cell infiltration, and fibrosis, NASH, at a molecular level, involves lipid-induced hepatocyte death and cytokine production. Currently, there are very few diagnostic biomarkers available to screen for NASH, and no pharmacological intervention is available for its treatment. In this study, we show that hepatocyte damage induced by lipotoxicity results in the release of extracellular RNAs (eRNAs), which serve as damage-associated molecular patterns (DAMPs) that stimulate the expression of pro-apoptotic and pro-inflammatory cytokines, aggravate inflammation, and lead to cell death in HepG2 cells. Furthermore, the inhibition of eRNA activity by RNase 1 significantly increases cellular viability and reduces NF-kB-mediated cytokine production. Similarly, RNase 1 administration significantly improves hepatic steatosis, inflammatory and injury markers in a murine NASH model. Therefore, this study, for the first time, underscores the therapeutic potential of inhibiting eRNA action as a novel strategy for NASH treatment.
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Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatócitos/metabolismo , Inflamação/patologia , CitocinasRESUMO
Cancer stem cells (CSCs) are a subset of cancer cells with self-renewal ability and tumor initiating properties. Unlike the other non-stem cancer cells, CSCs resist traditional therapy and remain a major cause of disease relapse. With the recent advances in metabolomics, various studies have demonstrated that CSCs have distinct metabolic properties. Metabolic reprogramming in CSCs contributes to self-renewal and maintenance of stemness. Accumulating evidence suggests that rewiring of energy metabolism is a key player that enables to meet energy demands, maintains stemness, and sustains cancer growth and invasion. CSCs use various mechanisms such as increased glycolysis, redox signaling, and autophagy modulation to overcome nutritional deficiency and sustain cell survival. The alterations in lipid metabolism acquired by the CSCs support biomass production through increased dependence on fatty acid synthesis and ß-oxidation, and contribute to oncogenic signaling pathways. This review summarizes our current understanding of lipid metabolism in CSCs and how pharmacological regulation of autophagy and lipid metabolism influences CSC phenotype. Increased dependence on lipid metabolism appears as an attractive strategy to eliminate CSCs using therapeutic agents that specifically target CSCs based on their modulation of lipid metabolism.
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Metabolismo dos Lipídeos , Neoplasias , Humanos , Metabolismo dos Lipídeos/fisiologia , Neoplasias/patologia , Metabolismo Energético , Células-Tronco Neoplásicas/patologia , AutofagiaRESUMO
Nonalcoholic steatohepatitis (NASH) is considered a pivotal stage in nonalcoholic fatty liver disease (NAFLD) progression and increases the risk of end-stage liver diseases such as fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The etiology of NASH is multifactorial and identifying reliable molecular players has proven difficult. Presently, there are no approved drugs for NASH treatment, which has become a leading cause of liver transplants worldwide. Here, using public human transcriptomic NAFLD dataset, we uncover Cystic fibrosis transmembrane conductance receptor (CFTR) as a differentially expressed gene in the livers of human NASH patients. Similarly, murine Cftr expression was also found to be upregulated in two mouse models of diet-induced NASH. Furthermore, the pharmacological inhibition of CFTR significantly reduced NASH progression in mice and its overexpression aggravated lipotoxicity in human hepatic cells. These results, thus, underscore the involvement of murine Cftr in the pathogenesis of NASH and raise the intriguing possibility of its pharmacological inhibition in human NASH.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Animais , Humanos , Camundongos , Carcinoma Hepatocelular/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose , Neoplasias Hepáticas/patologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismoRESUMO
Autophagy, a cellular degradative process, has emerged as a key regulator of cellular energy production and stress mitigation. Dysregulated autophagy is a common phenomenon observed in several human diseases, and its restoration offers curative advantage. Non-alcoholic fatty liver disease (NAFLD), more recently renamed metabolic dysfunction-associated steatotic liver disease, is a major metabolic liver disease affecting almost 30% of the world population. Unfortunately, NAFLD has no pharmacological therapies available to date. Autophagy regulates several hepatic processes including lipid metabolism, inflammation, cellular integrity and cellular plasticity in both parenchymal (hepatocytes) and non-parenchymal cells (Kupffer cells, hepatic stellate cells and sinusoidal endothelial cells) with a profound impact on NAFLD progression. Understanding cell type-specific autophagy in the liver is essential in order to develop targeted treatments for liver diseases such as NAFLD. Modulating autophagy in specific cell types can have varying effects on liver function and pathology, making it a promising area of research for liver-related disorders. This review aims to summarize our present understanding of cell-type specific effects of autophagy and their implications in developing autophagy centric therapies for NAFLD.
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Autophagy and telomere maintenance are two cellular survival processes that show a strong correlation during human ageing and cancer growth, however, their causal relationship remains unclear. In this study, using an unbiased transcriptomics approach, we uncover a novel role of autophagy genes in regulating telomere extension and maintenance pathways. Concomitantly, the pharmacological inhibition of ULK1 (Unc-51 like autophagy activating kinase 1) attenuated human telomerase reverse transcriptase (hTERT) gene expression and telomerase activity in HepG2 cells. Furthermore, the suppression of telomerase activity upon ULK1 inhibition was associated with telomere shortening and onset of cellular senescence in HepG2 cells. These results, thus, demonstrate a direct role of autophagy in maintaining cellular longevity via regulation of telomerase activity, which may have implications in the pathophysiology of ageing and cancers.
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Neoplasias , Telomerase , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Hepatócitos/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Telomerase/genética , Telomerase/metabolismo , Telômero/genética , Telômero/metabolismo , Encurtamento do TelômeroRESUMO
Autophagy inhibition is currently considered a novel therapeutic strategy for cancer treatment. Lipoic acid (LA), a naturally occurring compound found in all prokaryotic and eukaryotic cells, inhibits breast cancer cell growth; however, the effect of LA on autophagy-mediated breast cancer cell death remains unknown. Our study identified that LA blocks autophagic flux by inhibiting autophagosome-lysosome fusion and lysosome activity which increases the accumulation of autophagosomes in MCF-7 and MDA-MB231 cells, leading to cell death of breast cancer cells. Interestingly, autophagic flux blockade limits the recycling of cellular fuels, resulting in insufficient substrates for cellular bioenergetics. Therefore, LA impairs cellular bioenergetics by the inhibition of mitochondrial function and glycolysis. We show that LA-induced ROS generation is responsible for the blockade of autophagic flux and cellular bioenergetics in breast cancer cells. Moreover, LA-mediated blockade of autophagic flux and ROS generation may interfere with the regulation of the BCSCs/progenitor phenotype. Here, we demonstrate that LA inhibits mammosphere formation and subpopulation of BCSCs. Together, these results implicate that LA acts as a prooxidant, potent autophagic flux inhibitor, and causes energetic impairment, which may lead to cell death in breast cancer cells/BCSCs.
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Neoplasias , Ácido Tióctico , Autofagossomos/metabolismo , Autofagia , Metabolismo Energético , Neoplasias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ácido Tióctico/farmacologia , Ácido Tióctico/uso terapêuticoRESUMO
Liver is the primary organ for energy metabolism and detoxification in the human body. Not surprisingly, a derangement in liver function leads to several metabolic diseases. Autophagy is a cellular process, which primarily deals with providing molecules for energy production, and maintains cellular health. Autophagy in the liver has been implicated in several hepatic metabolic processes, such as, lipolysis, glycogenolysis, and gluconeogenesis. Autophagy also provides protection against drugs and pathogens. Deregulation of autophagy is associated with the development of non-alcoholic fatty liver disease (NAFLD) acute-liver injury, and cancer. The process of autophagy is synchronized by the action of autophagy family genes or autophagy (Atg) genes that perform key functions at different steps. The uncoordinated-51-like kinases 1 (ULK1) is a proximal kinase member of the Atg family that plays a crucial role in autophagy. Interestingly, ULK1 actions on hepatic cells may also involve some autophagy-independent signaling. In this review, we provide a comprehensive update of ULK1 mediated hepatic action involving lipotoxicity, acute liver injury, cholesterol synthesis, and hepatocellular carcinoma, including both its autophagic and non-autophagic functions.
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Chemokines are small secretory chemotactic cytokines that control the directed migration of immune cells. Chemokines are involved in both anti-and pro-tumorigenic immune responses. Accumulating evidence suggests that the balance between these responses is influenced by several factors such as the stage of tumorigenesis, immune cell activation, recruitment of immune activating or immunosuppressive cells in the tumor microenvironment (TME), and chemokine receptor expression on effector and regulatory target cells. Cancer cells engage in a complex network with their TME components via several factors including growth factors, cytokines and chemokines that are critical for the growth of primary tumor and metastasis. However, chemokines show a multifaceted role in tumor progression including maintenance of stem-like properties, tumor cell proliferation/survival/senescence, angiogenesis, and metastasis. The heterogeneity of solid tumors in primary and metastatic cancers presents a challenge to the development of successful cancer therapy. Despite extensive research on how solid tumors escape immune cell-mediated anti-tumor response, finding an effective therapy for metastatic cancer still remains a challenge. This review discusses the multifarious roles of chemokines in solid tumors including various chemokine signaling pathways such as CXCL8-CXCR1/2, CXCL9, 10, 11-CXCR3, CXCR4-CXCL12, CCL(X)-CCR(X) in primary and metastatic cancers. We further discuss the novel therapeutic approaches that have been developed by major breakthroughs in chemokine research to treat cancer patients by the strategic blockade/activation of these signaling axes alone or in combination with immunotherapies.
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Neoplasias , Humanos , Neoplasias/patologia , Microambiente Tumoral , Neovascularização Patológica , Imunoterapia , BiologiaRESUMO
Non-alcoholic steatohepatitis (NASH) is a clinically important spectrum of non-alcoholic fatty liver disease (NAFLD) in humans. NASH is a stage of NAFLD progression wherein liver steatosis accompanies inflammation and pro-fibrotic events. Presently, there are no approved drugs for NASH, which has become a leading cause of liver transplant worldwide. To discover novel drug targets for NASH, we analyzed a human transcriptomic NASH dataset and found Aldo-keto reductase family 1 member B10 (AKR1B10) as a significantly upregulated gene in livers of human NASH patients. Similarly murine Akr1b10 and Aldo-keto reductase family 1 member B8 (Akr1b8) gene, which is a murine ortholog of human AKR1B10, were also found to be upregulated in a mouse model of diet-induced NASH. Furthermore, pharmacological inhibitors of AKR1B10 significantly reduced the pathological features of NASH such as steatosis, inflammation and fibrosis in mouse. In addition, genetic silencing of both mouse Akr1b10 and Akr1b8 significantly reduced the expression of proinflammatory cytokines from hepatocytes. These results, thus, underscore the involvement of murine AKR1B10 and AKR1B8 in the pathogenesis of murine NASH and raise an intriguing possibility of a similar role of AKR1B10 in human NASH.
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Oxirredutases do Álcool/metabolismo , Aldo-Ceto Redutases/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Oxirredutases do Álcool/antagonistas & inibidores , Oxirredutases do Álcool/genética , Aldo-Ceto Redutases/antagonistas & inibidores , Aldo-Ceto Redutases/genética , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Linhagem Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Hepatócitos/citologia , Hepatócitos/metabolismo , Humanos , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/etiologia , Cirrose Hepática/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Sulindaco/uso terapêuticoRESUMO
The liver is an organ of vital importance in the body; it is the center of metabolic activities and acts as the primary line of defense against toxic compounds. Exposure to environmental toxicants is an unavoidable fallout from rapid industrialization across the world and is even higher in developing countries. Technological development and industrialization have led to the release of toxicants such as pollutant toxic gases, chemical discharge, industrial effluents, pesticides and solvents, into the environment. In the last few years, a growing body of evidence has shed light on the potential impact of environmental toxicants on liver health, in particular, on non-alcoholic fatty liver disease (NAFLD) incidence and progression. NAFLD is a multifactorial disease linked to metabolic derangement including diabetes and other complications. Environmental toxicants including xenobiotics and pollutants may have a direct or indirect steatogenic/fibrogenic impact on the liver and should be considered as risk factors associated with NAFLD. This review discusses the contribution of environmental toxicants toward the increasing disease burden of NAFLD.
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Hepatopatia Gordurosa não Alcoólica , Efeitos Psicossociais da Doença , Humanos , Incidência , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Fatores de RiscoRESUMO
The incidence of non-alcoholic fatty liver disease (NAFLD) is rising rapidly across the globe. NAFLD pathogenesis is largely driven by an imbalance in hepatic energy metabolism and at present, there is no approved drug for its treatment. The liver plays a crucial role in micronutrient metabolism and deregulation of this micronutrient metabolism may contribute to the pathogenesis of NAFLD. Vitamins regulate several enzymatic processes in the liver, and derangement in vitamin metabolism is believed to play a critical role in NAFLD progression. The anti-oxidant activities of vitamin C and E have been attributed to mitigate hepatocyte injury, and alterations in the serum levels of vitamin D, vitamin B12 and folate have shown a strong correlation with NAFLD severity. This review aims to highlight the role of these vitamins, which represent promising therapeutic targets for the management of NAFLD.
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OBJECTIVE: Crinophagy is a secretory granule-specific autophagic process that regulates hormone content and secretion in endocrine cells. However, despite being one of the earliest described autophagic processes, its mechanism of action and regulation in mammalian cells remains unclear. METHODS AND RESULTS: Here, we examined mammalian crinophagy and its modulation that regulate hormone secretion in a glucagon-producing mouse pancreatic α-cell line, alpha TC1 clone 9 (αTC9), and in vivo. Western blot, electron microscopy, and immunofluorescence analyses were performed to study crinophagy and glucagon secretion in αTC9 cells and C57BL/6 mice, in response to the mammalian target of rapamycin complex 1 (MTORC1) inhibitor rapamycin. Amino acid depletion and pharmacological inhibition of MTORC1 increased the shuttling of glucagon-containing secretory granules into lysosomes for crinophagic degradation to reduce glucagon secretion through a macroautophagy-independent mechanism. Furthermore, MTORC1 inhibition reduced both intracellular and secreted glucagon in rapamycin-treated mice, in response to hypoglycaemia. CONCLUSION: In summary, we have identified a novel crinophagic mechanism of intracellular glucagon turnover in pancreatic α-cells regulated by MTORC1 signalling.
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Autofagia , Glucagon/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Vesículas Secretórias/metabolismo , Animais , Células Cultivadas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos TransgênicosRESUMO
BACKGROUND: Double-fortified salt (DFS) with iron and iodine has been demonstrated to be efficacious but questions of unintended effects on the gains in salt iodization remain. The main cross-sectional study based on the use of DFS over 1 y showed a reduction in iron deficiency risk. Whether the programs and the levels of added iron can adversely affect iodine status is yet to be established. OBJECTIVES: We hypothesized that the addition of iron to iodized salt can adversely affect iodine status in women of reproductive age (WRA). METHODS: A cross-sectional substudy was conducted in 4 matched-pair adjacent districts of rural Uttar Pradesh, India, in 2019. Under the public distribution system (PDS), DFS was available for 1 y through Fair Price Shops, in the 2 DFS supply districts (DFS-SDs). In these districts, iodized salt was also available in the market. In the 2 compared DFS nonsupply districts (DFS-NSDs), only iodized salt was available. In the substudy, participants included WRA (n = 1624) residing in rural areas of the selected districts. Iodine content in urine and salt samples was measured in each of the groups. RESULTS: Significantly fewer women from the DFS-SDs had median urinary iodine concentration values indicative of moderate to mild iodine deficiency compared with the women from the DFS-NSDs. The salt purchase pattern and iodine content revealed that significantly fewer (21.99%) households in the DFS-SDs were purchasing inadequately iodized crystal salt, compared with 36.04% households in the DFS-NSDs. CONCLUSIONS: The data reject the working hypothesis and suggest a beneficial effect of the DFS program on the iodine status in WRA, thereby supporting a recommendation of DFS supply through the PDS.
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Non-alcoholic fatty liver disease (NAFLD) is one the fastest emerging manifestations of the metabolic syndrome worldwide. Non-alcoholic steatohepatitis (NASH), the progressive form of NAFLD, may culminate into cirrhosis and hepatocellular cancer (HCC) and is presently a leading cause of liver transplant. Although a steady progress is seen in understanding of the disease epidemiology, pathogenesis and identifying therapeutic targets, the slowest advancement is seen in the therapeutic field. Currently, there is no FDA approved therapy for this disease and appropriate therapeutic targets are urgently warranted. In this review we discuss the role of lifestyle intervention, pharmacological agents, surgical approaches, and gut microbiome, with regard to therapy for NASH. In particular, we focus the role of insulin sensitizers, thyroid hormone mimetics, antioxidants, cholesterol lowering drugs, incretins and cytokines as therapeutic targets for NASH. We highlight these targets aiming to optimize the future for NASH therapy.
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Hepatopatia Gordurosa não Alcoólica/terapia , Carcinoma Hepatocelular/patologia , Progressão da Doença , Microbioma Gastrointestinal , Humanos , Estilo de Vida , Cirrose Hepática/patologia , Neoplasias Hepáticas/patologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/cirurgiaRESUMO
Hepatocellular cancer (HCC) is one of the leading causes of mortality worldwide. Unfortunately, a limited choice of anti-cancer drugs is available for treatment, owing to their minimal efficacy and development of acquired resistance. Autophagy, a cellular survival pathway, often exhibits a pleiotropic role in HCC progression. Studies show increased autophagy in established HCC, promoting the survival of HCC cells in the tumour microenvironment. Therefore, novel anti-autophagy drugs hold promise for preventing HCC progression. Here, using a non-biased transcriptomics analysis in HepG2 cells we demonstrate the existence of an autophagy-FOXM1 nexus regulating growth in HepG2 cells. Additionally, we show that suppression of autophagy by an Unc-51 Like Autophagy Activating Kinase 1(ULK1) inhibitor not only attenuates the expression of FOXM1 and its transcriptional targets, but also has a synergistic effect on the inhibition of HepG2 growth when combined with FOXM1 inhibitors. Thus, the autophagic protein, ULK1, is a promising candidate for preventing HCC progression. Collectively, our results provide new insight into the role of autophagy in HCC growth and are a proof-of concept for combinatorial therapy using ULK1 and FOXM1 inhibitors.
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Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Autofagia , Carcinoma Hepatocelular/metabolismo , Proteína Forkhead Box M1/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Hepáticas/metabolismo , Autofagia/genética , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/antagonistas & inibidores , Carcinoma Hepatocelular/genética , Proliferação de Células , Proteína Forkhead Box M1/antagonistas & inibidores , Inativação Gênica , Células Hep G2 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Neoplasias Hepáticas/genética , Transdução de Sinais/efeitos dos fármacosRESUMO
Non-alcoholic fatty liver disease (NAFLD) and its advanced complication, non-alcoholic steatohepatitis (NASH), have become leading causes of hepatocellular carcinoma (HCC) worldwide. In this review, we discuss the role of metabolic, gut microbial, immune and endocrine mediators which promote the progression of NAFLD to HCC. In particular, this progression involves multiple hits resulting from lipotoxicity, oxidative stress, inhibition of hepatic autophagy and inflammation. Furthermore, dysbiosis in the gut associated with obesity also promotes HCC via induction of proinflammatory cytokines and Toll like receptor signalling as well as altered bile metabolism. Additionally, compromised T-cell function and impaired hepatic hormonal action promote the development of NASH-associated HCC. Lastly, we discuss the current challenges involved in the diagnosis and treatment of NAFLD/NASH-associated HCC.