Hepatic SIRT6 deficit promotes liver tumorigenesis in the mice models.
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ABSTRACT:
SUBMITTER: Wang M
PROVIDER: S-EPMC9243323 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundSirtuin 6 (SIRT6) is a NAD+-dependent deacetylase with key roles in cell metabolism. High SIRT6 expression is associated with adverse prognosis in breast cancer (BC) patients. However, the mechanisms through which SIRT6 exerts its pro-oncogenic effects in BC remain unclear. Here, we sought to define the role of SIRT6 in BC cell metabolism and in mouse polyoma middle T antigen (PyMT)-driven mammary tumors.MethodsWe evaluated the effect of a heterozygous deletion of Sirt6 on tumor latency and survival of mouse mammary tumor virus (MMTV)-PyMT mice. The effect of SIRT6 silencing on human BC cell growth was assessed in MDA-MB-231 xenografts. We also analyzed the effect of Sirt6 heterozygous deletion, of SIRT6 silencing, and of the overexpression of either wild-type (WT) or catalytically inactive (H133Y) SIRT6 on BC cell pyruvate dehydrogenase (PDH) expression and activity and oxidative phosphorylation (OXPHOS), including respiratory complex activity, ATP/AMP ratio, AMPK activation, and intracellular calcium concentration.ResultsThe heterozygous Sirt6 deletion extended tumor latency and mouse survival in the MMTV-PyMT mouse BC model, while SIRT6 silencing slowed the growth of MDA-MB-231 BC cell xenografts. WT, but not catalytically inactive, SIRT6 enhanced PDH expression and activity, OXPHOS, and ATP/AMP ratio in MDA-MB-231 and MCF7 BC cells. Opposite effects were obtained by SIRT6 silencing, which also blunted the expression of genes encoding for respiratory chain proteins, such as UQCRFS1, COX5B, NDUFB8, and UQCRC2, and increased AMPK activation in BC cells. In addition, SIRT6 overexpression increased, while SIRT6 silencing reduced, intracellular calcium concentration in MDA-MB-231 cells. Consistent with these findings, the heterozygous Sirt6 deletion reduced the expression of OXPHOS-related genes, the activity of respiratory complexes, and the ATP/AMP ratio in tumors isolated from MMTV-PyMT mice.ConclusionsVia its enzymatic activity, SIRT6 enhances PDH expression and activity, OXPHOS, ATP/AMP ratio, and intracellular calcium concentration, while reducing AMPK activation, in BC cells. Thus, overall, SIRT6 inhibition appears as a viable strategy for preventing or treating BC.
| S-EPMC7821730 | biostudies-literature
Project description:The pro-longevity enzyme SIRT6 regulates various metabolic pathways. Gene expression analyses in SIRT6 heterozygotic mice identify significant decreases in PPAR? signaling, known to regulate multiple metabolic pathways. SIRT6 binds PPAR? and its response element within promoter regions and activates gene transcription. Sirt6+/- results in significantly reduced PPAR?-induced ?-oxidation and its metabolites and reduced alanine and lactate levels, while inducing pyruvate oxidation. Reciprocally, starved SIRT6 transgenic mice show increased pyruvate, acetylcarnitine, and glycerol levels and significantly induce ?-oxidation genes in a PPAR?-dependent manner. Furthermore, SIRT6 mediates PPAR? inhibition of SREBP-dependent cholesterol and triglyceride synthesis. Mechanistically, SIRT6 binds PPAR? coactivator NCOA2 and decreases liver NCOA2 K780 acetylation, which stimulates its activation of PPAR? in a SIRT6-dependent manner. These coordinated SIRT6 activities lead to regulation of whole-body respiratory exchange ratio and liver fat content, revealing the interactions whereby SIRT6 synchronizes various metabolic pathways, and suggest a mechanism by which SIRT6 maintains healthy liver.
| S-EPMC7165364 | biostudies-literature
Project description:The liver is a major organ in lipid metabolism, and its malfunction leads to various diseases. Nonalcoholic fatty liver disease, the most common chronic liver disorder in developed countries, is characterized by the abnormal retention of excess lipid within hepatocytes and predisposes individuals to liver cancer. We previously reported that the levels of Lissencephaly 1 (LIS1, also known as PAFAH1B1) are down-regulated in human hepatocellular carcinoma. Following up on this observation, we found that genetic deletion of Lis1 in the mouse liver increases lipid accumulation and inflammation in this organ. Further analysis revealed that loss of Lis1 triggers endoplasmic reticulum (ER) stress and reduces triglyceride secretion. Attenuation of ER stress by addition of tauroursodeoxycholic acid (TUDCA) diminished lipid accumulation in the Lis1-deficient hepatocytes. Moreover, the Golgi stacks were disorganized in Lis1-deficient liver cells. Of note, the Lis1 liver-knockout mice exhibited increased hepatocyte ploidy and accelerated development of liver cancer after exposure to the liver carcinogen diethylnitrosamine (DEN). Taken together, these findings suggest that reduced Lis1 levels can spur the development of liver diseases from steatosis to liver cancer and provide a useful model for delineating the molecular pathways that lead to these diseases.
| S-EPMC5892582 | biostudies-literature
Project description:Non-alcoholic fatty liver disease has become one of the most common causes of chronic liver disease that can develop into a more serious form, non-alcoholic steatohepatitis, leading to liver cirrhosis and hepatocellular carcinoma. Although hepatic retinoid stores are progressively lost during the development of liver disease, how this affects steatohepatitis and its related hepatocarcinogenesis is unknown. In order to investigate these, we used subcutaneous injection of streptozotocin (0.2 mg/body) and high-fat diet to induce steatohepatitis and hepatic tumorigenesis in lecithin:retinol acyltransferase -deficient mice (n = 10), which lack stored retinoid in the liver, and control mice (n = 12). At the termination of the experiment (16 weeks of age), the development of hepatic tumors was significantly suppressed in mutant mice compared to controls. Lower serum levels of alanine aminotransferase and decreased hepatic levels of cyclin D1 were observed in mutant mice. Mutant mice exhibited increased levels of retinoic acid-responsive genes, including p21, and decreased oxidative stress as evaluated by serum and liver markers. Our findings are consistent with the conclusion that mutant mice are less susceptible to steatohepatitis-related liver tumorigenesis due to increased retinoid signaling, which is accompanied by up-regulated p21 expression and attenuated oxidative stress.
| S-EPMC5642587 | biostudies-literature
Project description:The crosstalk between deregulated hepatocyte metabolism and cells within the tumour microenvironment, as well as the consequent effects on liver tumorigenesis, are not completely understood. We show here that hepatocyte-specific loss of the gluconeogenic enzyme fructose 1,6-bisphosphatase 1 (FBP1) disrupts liver metabolic homeostasis and promotes tumour progression. FBP1 is universally silenced in both human and murine liver tumours. Hepatocyte-specific Fbp1 deletion results in steatosis, concomitant with activation and senescence of hepatic stellate cells (HSCs), exhibiting a senescence-associated secretory phenotype. Depleting senescent HSCs by 'senolytic' treatment with dasatinib/quercetin or ABT-263 inhibits tumour progression. We further demonstrate that FBP1-deficient hepatocytes promote HSC activation by releasing HMGB1; blocking its release with the small molecule inflachromene limits FBP1-dependent HSC activation, the subsequent development of the senescence-associated secretory phenotype and tumour progression. Collectively, these findings provide genetic evidence for FBP1 as a metabolic tumour suppressor in liver cancer and establish a critical crosstalk between hepatocyte metabolism and HSC senescence that promotes tumour growth.
| S-EPMC7286794 | biostudies-literature
Project description:Under various conditions, mammals have the ability to maintain serum glucose concentration within a narrow range. SIRT1 plays an important role in regulating gluconeogenesis and fat metabolism; however, the underlying mechanisms remain elusive. Here, we show that SIRT1 forms a complex with FOXO3a and NRF1 on the SIRT6 promoter and positively regulates expression of SIRT6, which, in turn, negatively regulates glycolysis, triglyceride synthesis, and fat metabolism by deacetylating histone H3 lysine 9 in the promoter of many genes involved in these processes. Liver-specific deletion of SIRT6 in mice causes profound alterations in gene expression, leading to increased glycolysis, triglyceride synthesis, reduced beta oxidation, and fatty liver formation. Human fatty liver samples exhibited significantly lower levels of SIRT6 than did normal controls. Thus, SIRT6 plays a critical role in fat metabolism and may serve as a therapeutic target for treating fatty liver disease, the most common cause of liver dysfunction in humans.
| S-EPMC2935915 | biostudies-literature
Project description:Autophagy is an intracellular lysosomal degradation process that plays an important role in regulating normal physiological functions of the liver. The purpose of the present study was to investigate the mechanism(s) by which the loss of hepatic autophagy leads to liver inflammation, fibrosis and tumorigenesis.Hepatocyte-specific Atg5 knockout mice were generated by crossing Atg5 Flox/Flox mice with albumin Cre mice. These mice were also crossed with Nrf2 knockout mice to generate Atg5 Flox/Flox, Albumin Cre(+)/Nrf2(-/-) double knockout mice. These mice were housed for various time points up to 15 months, and blood and liver tissues were harvested for biochemical and histological analysis.Hepatocyte-specific deletion of Atg5 resulted in increased apoptosis, inflammation and fibrosis in the liver. Increased apoptosis in hepatocyte-specific Atg5 knockout mice was likely due to accumulation of aberrant polyubiquitinated proteins (proteotoxicity) and disruption of the homeostasis of pro-and anti-apoptotic proteins. All of these pathological changes started as early as one month and persisted for 12-15 months. At 9-15 months of age, these mice also developed hepatocellular adenomas. Interestingly, deletion of Nrf2 in Atg5 liver-specific knockout mice markedly abolished these pathological changes, indicating a key role for this transcription factor in the mechanism of hepatic pathology.Our results provide genetic evidence that loss of autophagy in hepatocytes causes cell death resulting in liver inflammation, fibrosis and tumorigenesis. We also demonstrate that persistent activation of Nrf2 is critical for liver inflammation, fibrosis and eventual tumorigenesis that occur in mice with defects in hepatocyte autophagy.
| S-EPMC4143992 | biostudies-other
Project description:Hepatocellular carcinoma (HCC) develops as a consequence of chronic inflammatory liver diseases such as chronic hepatitis B virus (HBV) infection. The transcription factor c-Jun/activator protein 1 (AP-1) is strongly expressed in response to inflammatory stimuli, promotes hepatocyte survival during acute hepatitis and acts as an oncogene during chemically induced liver carcinogenesis in mice. Here, we therefore aimed to characterize the functions of c-Jun during HBV-related liver tumorigenesis. To this end, transgenic mice expressing all HBV envelope proteins (HBV(+)), an established model of HBV-related HCC, were crossed with knockout mice lacking c-Jun specifically in hepatocytes and tumorigenesis was analyzed. Hepatic expression of c-Jun was strongly induced at several time points during tumorigenesis in HBV(+) mice, whereas expression of other AP-1 components remained unchanged. Importantly, formation of premalignant foci and tumors was strongly reduced in HBV(+) mice lacking c-Jun. This phenotype correlated with impaired hepatocyte proliferation and increased expression of the cell cycle inhibitor p21, whereas hepatocyte survival was not affected. Progression and prognosis of HBV-related HCC correlates with the expression of the cytokine osteopontin (Opn), an established AP-1 target gene. Opn expression was strongly reduced in HBV(+) livers and primary mouse hepatocytes lacking c-Jun, demonstrating that c-Jun regulates hepatic Opn expression in a cell-autonomous manner. These findings indicate that c-Jun has important functions during HBV-associated tumorigenesis by promoting hepatocyte proliferation as well as progression of dysplasia. Therefore, targeting c-Jun may be a useful strategy to prevent hepatitis-associated tumorigenesis.
| S-EPMC4986630 | biostudies-literature
Project description:Hepatic fibrosis arises from inflammation in the liver initiated by resident macrophage activation and massive leukocyte accumulation. Hepatic macrophages hold a central position in maintaining homeostasis in the liver and in the pathogenesis of acute and chronic liver injury linked to fibrogenesis. Interferon regulatory factor 5 (IRF5) has recently emerged as an important proinflammatory transcription factor involved in macrophage activation under acute and chronic inflammation. Here, we revealed that IRF5 is significantly induced in liver macrophages from human subjects developing liver fibrosis from nonalcoholic fatty liver disease or hepatitis C virus infection. Furthermore, IRF5 expression positively correlated with clinical markers of liver damage, such as plasma transaminase and bilirubin levels. Interestingly, mice lacking IRF5 in myeloid cells (MKO) were protected from hepatic fibrosis induced by metabolic or toxic stresses. Transcriptional reprogramming of macrophages lacking IRF5 was characterized by immunosuppressive and antiapoptotic properties. Consequently, IRF5 MKO mice respond to hepatocellular stress by promoting hepatocyte survival, leading to complete protection from hepatic fibrogenesis. Our findings reveal a regulatory network, governed by IRF5, that mediates hepatocyte death and liver fibrosis in mice and humans. Therefore, modulating IRF5 function may be an attractive approach to experimental therapeutics in fibroinflammatory liver disease.
| S-EPMC5135279 | biostudies-literature
Project description:Excess consumption of trans-fatty acid (TFA), an unsaturated fatty acid containing trans double bonds, is a major risk factor for cardiovascular disease and metabolic syndrome. However, little is known about the link between TFA and hepatocellular carcinoma (HCC) despite it being a frequent form of cancer in humans. In this study, the impact of excessive dietary TFA on hepatic tumorigenesis was assessed using hepatitis C virus (HCV) core gene transgenic mice that spontaneously developed HCC. Male transgenic mice were treated for 5 months with either a control diet or an isocaloric TFA-rich diet that replaced the majority of soybean oil with shortening. The prevalence of liver tumors was significantly higher in TFA-rich diet-fed transgenic mice compared with control diet-fed transgenic mice. The TFA-rich diet significantly increased the expression of pro-inflammatory cytokines, as well as oxidative and endoplasmic reticulum stress, and activated nuclear factor-kappa B (NF-κB) and nuclear factor erythroid 2-related factor 2 (NRF2), leading to high p62/sequestosome 1 (SQSTM1) expression. Furthermore, the TFA diet activated extracellular signal-regulated kinase (ERK) and stimulated the Wnt/β-catenin signaling pathway, synergistically upregulating cyclin D1 and c-Myc, driving cell proliferation. Excess TFA intake also promoted fibrogenesis and ductular reaction, presumably contributing to accelerated liver tumorigenesis. In conclusion, these results demonstrate that a TFA-rich diet promotes hepatic tumorigenesis, mainly due to persistent activation of NF-κB and NRF2-p62/SQSTM1 signaling, ERK and Wnt/β-catenin pathways and fibrogenesis. Therefore, HCV-infected patients should avoid a TFA-rich diet to prevent liver tumor development.
| S-EPMC8456504 | biostudies-literature