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1.
Clin Transl Med ; 11(4): e379, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33931972

RESUMO

BACKGROUND AND AIMS: 4-phenylbutyric acid (4-PBA) is a low molecular weight fatty acid that is used in clinical practice to treat inherited urea cycle disorders. In previous reports, it acted as a chemical chaperone inhibiting endoplasmic reticulum (ER) stress and unfolded protein response signaling. A few studies have suggested its function against hepatic fibrosis in mice models. However, its role in hepatocarcinogenesis remained unknown. METHODS: 4-PBA was administered alone or in combination with diethylnitrosamine to investigate its long-term effect on liver tumorigenesis. The role of 4-PBA in oncogene-induced hepatocellular carcinoma (HCC) mice model using sleeping beauty system co-expressed with hMet and ß-catenin point mutation (S45Y) was also observed. RNA-seq and PCR array were used to screen the pathways and genes involved. In vitro and in vivo studies were conducted to explore the effect of 4-PBA on liver and validate the underlying mechanism. RESULTS: 4-PBA alone didn't cause liver tumor in long term. However, it promoted liver tumorigenesis in HCC mice models via initiation of liver cancer stem cells (LCSCs) through Wnt5b-Fzd5 mediating ß-catenin signaling. Peroxisome proliferator-activated receptors (PPAR)-α induced by 4-PBA was responsible for the activation of ß-catenin signaling. Thus, intervention of PPAR-α reversed 4-PBA-induced initiation of LCSCs and HCC development in vivo. Further study revealed that 4-PBA could not only upregulate the expression of PPAR-α transcriptionally but also enhance its stabilization via protecting it from proteolysis. Moreover, high PPAR-α expression predicted poor prognosis in HCC patients. CONCLUSIONS: 4-PBA could upregulate PPAR-α to initiate LCSCs by activating ß-catenin signaling pathway, promoting HCC at early stage. Therefore, more discretion should be taken to monitor the potential tumor-promoting effect of 4-PBA under HCC-inducing environment.

2.
Am J Pathol ; 191(5): 885-901, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33662348

RESUMO

Hepatocytes are highly polarized epithelia. Loss of hepatocyte polarity is associated with various liver diseases, including cholestasis. However, the molecular underpinnings of hepatocyte polarization remain poorly understood. Loss of ß-catenin at adherens junctions is compensated by γ-catenin and dual loss of both catenins in double knockouts (DKOs) in mice liver leads to progressive intrahepatic cholestasis. However, the clinical relevance of this observation, and further phenotypic characterization of the phenotype, is important. Herein, simultaneous loss of ß-catenin and γ-catenin was identified in a subset of liver samples from patients of progressive familial intrahepatic cholestasis and primary sclerosing cholangitis. Hepatocytes in DKO mice exhibited defects in apical-basolateral localization of polarity proteins, impaired bile canaliculi formation, and loss of microvilli. Loss of polarity in DKO livers manifested as epithelial-mesenchymal transition, increased hepatocyte proliferation, and suppression of hepatocyte differentiation, which was associated with up-regulation of transforming growth factor-ß signaling and repression of hepatocyte nuclear factor 4α expression and activity. In conclusion, concomitant loss of the two catenins in the liver may play a pathogenic role in subsets of cholangiopathies. The findings also support a previously unknown role of ß-catenin and γ-catenin in the maintenance of hepatocyte polarity. Improved understanding of the regulation of hepatocyte polarization processes by ß-catenin and γ-catenin may potentially benefit development of new therapies for cholestasis.


Assuntos
Colestase Intra-Hepática/patologia , Fator 4 Nuclear de Hepatócito/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , beta Catenina/metabolismo , gama Catenina/metabolismo , Junções Aderentes/metabolismo , Animais , Linhagem Celular Tumoral , Polaridade Celular , Fator 4 Nuclear de Hepatócito/genética , Hepatócitos/metabolismo , Humanos , Fígado/metabolismo , Camundongos , Camundongos Knockout , Fator de Crescimento Transformador beta/genética , beta Catenina/genética , gama Catenina/economia , gama Catenina/genética
3.
Mol Cell Biol ; 41(4)2021 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-33526450

RESUMO

IQ motif-containing GTPase-activating protein 1 (IQGAP1) is a ubiquitously expressed scaffolding protein that is overexpressed in a number of cancers, including liver cancer, and is associated with protumorigenic processes, such as cell proliferation, motility, and adhesion. IQGAP1 can integrate multiple signaling pathways and could be an effective antitumor target. Therefore, we examined the role of IQGAP1 in tumor initiation and promotion during liver carcinogenesis. We found that ectopic overexpression of IQGAP1 in the liver is not sufficient to initiate tumorigenesis. Moreover, we report that the tumor burden and cell proliferation in the diethylnitrosamine-induced liver carcinogenesis model in Iqgap1-/- mice may be driven by MET signaling. In contrast, IQGAP1 overexpression enhanced YAP activation and subsequent NUAK2 expression to accelerate and promote hepatocellular carcinoma (HCC) in a clinically relevant model expressing activated (S45Y) ß-catenin and MET. Here, increasing IQGAP1 expression in vivo does not alter ß-catenin or MET activation; instead, it promotes YAP activity. Overall, we demonstrate that although IQGAP1 expression is not required for HCC development, the gain of IQGAP1 function promotes the rapid onset and increased liver carcinogenesis. Our results show that an adequate amount of IQGAP1 scaffold is necessary to maintain the quiescent status of the liver.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Carcinoma Hepatocelular/metabolismo , Proteínas de Ciclo Celular/metabolismo , Transformação Celular Neoplásica/genética , Proteínas Ativadoras de ras GTPase/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinoma Hepatocelular/genética , Proteínas de Ciclo Celular/genética , Movimento Celular/genética , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Regulação Neoplásica da Expressão Gênica/genética , Fígado/metabolismo , Neoplasias Hepáticas/genética , Camundongos Knockout , Proteínas Ativadoras de ras GTPase/genética
4.
Hepatology ; 2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33529367

RESUMO

BACKGROUND: Hepatocellular cancer (HCC) remains a major unmet clinical need. Although activating CTNNB1 mutations are seen in prominent subsets of HCC cases, these by themselves are insufficient for hepatocarcinogenesis. Co-expression of mutant CTNNB1 with clinically relevant co-occurrence has yielded HCCs. Here, we identify cooperation between ß-catenin and Nrf2 signaling in HCC. METHODS: Public HCC datasets were assessed for concomitant presence of CTNNB1 mutations and either mutations in NFE2L2 or KEAP1, or Nrf2 activation by gene signature. HCC development in mice and similarity to human HCC subsets was assessed following co-expression of T41A-CTNNB1 with either WT-, G31A- or T80K-NFE2L2. Based on mTORC1 activation in CTNNB1-mutated HCCs, response of preclinical HCC to mTOR inhibitor was investigated. RESULTS: Overall, 9% of HCC cases showed concomitant CTNNB1 mutations and Nrf2 activation, subsets of which were due to mutations in NFE2L2/KEAP1. Co-expression of mutated-CTNNB1 with mutant-NFE2L2 but not WT-NFE2L2 led to HCC development and mortality by 12-14 weeks. These HCCs were positive for ß-catenin targets like Glutamine synthetase and Cyclin-D1, and Nrf2 targets like NAD(P)H Quinone Dehydrogenase 1 and peroxiredoxin 1. RNA-seq and pathway analysis showed high concordance of preclinical HCC to human HCC subset showing activation of unique (Iron Homeostasis and Glioblastoma Multiforme signaling) and expected (Glutamine Metabolism) pathways. NFE2L2-CTNNB1 HCC mice were treated with mTOR inhibitor everolimus (5mg/kg diet ad libitum), which led to >50% decrease in tumor burden. Conclusion Co-activation of ß-catenin and Nrf2 is evident in 9% of all human HCCs. Co-expression of mutant-NFE2L2 and mutant-CTNNB1 led to clinically relevant HCC development in mice, which responded to mTOR inhibitors. Thus, this model has both biological and therapeutic implications.

5.
J Hepatol ; 75(1): 120-131, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33577921

RESUMO

BACKGROUND & AIMS: Gain of function (GOF) mutations in the CTNNB1 gene are one of the most frequent genetic events in hepatocellular carcinoma (HCC). T-box transcription factor 3 (TBX3) is a liver-specific target of the Wnt/ß-catenin pathway and thought to be an oncogene mediating activated ß-catenin-driven HCC formation. METHODS: We evaluated the expression pattern of TBX3 in human HCC specimens. Tbx3 was conditionally knocked out in murine HCC models by hydrodynamic tail vein injection of Cre together with c-Met and ΔN90-ß-catenin (c-Met/ß-catenin) in Tbx3flox/flox mice. TBX3 was overexpressed in human HCC cell lines to investigate the functions of TBX3 in vitro. RESULTS: A bimodal expression pattern of TBX3 in human HCC samples was detected: high expression of TBX3 in GOF CTNNB1 HCC and downregulation of TBX3 in non-CTNNB1 mutant tumors. High expression of TBX3 was associated with increased differentiation and decreased expression signatures of tumor growth. Using Tbx3flox/flox mice, we found that ablation of Tbx3 significantly accelerates c-Met/ß-catenin-driven HCC formation. Moreover, Tbx3(-) HCC demonstrated increased YAP/TAZ activity. The accelerated tumor growth induced by loss of TBX3 in c-Met/ß-catenin mouse HCC was successfully prevented by overexpression of LATS2, which inhibited YAP/TAZ activity. In human HCC cell lines, overexpression of TBX3 inhibited HCC cell growth as well as YAP/TAZ activation. A negative correlation between TBX3 and YAP/TAZ target genes was observed in human HCC samples. Mechanistically, phospholipase D1 (PLD1), a known positive regulator of YAP/TAZ, was identified as a novel transcriptional target repressed by TBX3. CONCLUSION: Our study suggests that TBX3 is induced by GOF CTNNB1 mutants and suppresses HCC growth by inactivating PLD1, thus leading to the inhibition of YAP/TAZ oncogenes. LAY SUMMARY: TBX3 is a liver-specific target of the Wnt/ß-catenin pathway and thought to be an oncogene in promoting liver cancer development. Herein, we demonstrate that TBX3 is in fact a tumor suppressor gene that restricts liver tumor growth. Strategies which increase TBX3 expression and/or activities may be effective for HCC treatment.

6.
Nat Chem Biol ; 17(3): 298-306, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33495648

RESUMO

The adenosine monophosphate (AMP)-activated protein kinase (Ampk) is a central regulator of metabolic pathways, and increasing Ampk activity has been considered to be an attractive therapeutic target. Here, we have identified an orphan ubiquitin E3 ligase subunit protein, Fbxo48, that targets the active, phosphorylated Ampkα (pAmpkα) for polyubiquitylation and proteasomal degradation. We have generated a novel Fbxo48 inhibitory compound, BC1618, whose potency in stimulating Ampk-dependent signaling greatly exceeds 5-aminoimidazole-4-carboxamide-1-ß-ribofuranoside (AICAR) or metformin. This compound increases the biological activity of Ampk not by stimulating the activation of Ampk, but rather by preventing activated pAmpkα from Fbxo48-mediated degradation. We demonstrate that, consistent with augmenting Ampk activity, BC1618 promotes mitochondrial fission, facilitates autophagy and improves hepatic insulin sensitivity in high-fat-diet-induced obese mice. Hence, we provide a unique bioactive compound that inhibits pAmpkα disposal. Together, these results define a new pathway regulating Ampk biological activity and demonstrate the potential utility of modulating this pathway for therapeutic benefit.


Assuntos
Proteínas Quinases Ativadas por AMP/genética , Hipoglicemiantes/farmacologia , Obesidade/tratamento farmacológico , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Ubiquitina-Proteína Ligases/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/farmacologia , Animais , Linhagem Celular Transformada , Dieta Hiperlipídica , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Hipoglicemiantes/síntese química , Resistência à Insulina , Metformina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Dinâmica Mitocondrial/efeitos dos fármacos , Obesidade/etiologia , Obesidade/genética , Obesidade/metabolismo , Fosforilação , Poliubiquitina/genética , Poliubiquitina/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Estabilidade Proteica/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Ribonucleotídeos/farmacologia , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
7.
Gene Expr ; 20(3): 189-199, 2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-33472727

RESUMO

The liver is uniquely bestowed with an ability to regenerate following a surgical or toxicant insult. One of the most researched models to demonstrate the regenerative potential of this organ is the partial hepatectomy model, where two thirds of the liver is surgically resected. The remnant liver replenishes the lost mass within 1014 days in mice. The distinctive ability of the liver to regenerate has allowed living donor and split liver transplantation. One signaling pathway shown to be activated during the process of regeneration to contribute toward the mass and functional recovery of the liver is the Wnt/-catenin pathway. Very early after any insult to the liver, the cellmolecule circuitry of the Wnt/-catenin pathway is set into motion with the release of specific Wnt ligands from sinusoidal endothelial cells and macrophages, which, in a paracrine manner, engage Frizzled and LDL-related protein-5/6 coreceptors on hepatocytes to stabilize -catenin inducing its nuclear translocation. Nuclear -catenin interacts with T-cell factor family of transcription factors to induce target genes including cyclin D1 for proliferation, and others for regulating hepatocyte function. Working in collaboration with other signaling pathways, Wnt/-catenin signaling contributes to the restoration process without any compromise of function at any stage. Also, stimulation of this pathway through innovative means induces liver regeneration when this process is exhausted or compromised and thus has applications in the treatment of end-stage liver disease and in the field of liver transplantation. Thus, Wnt/-catenin signaling pathway is highly relevant in the discipline of hepatic regenerative medicine.

8.
Nat Commun ; 11(1): 5785, 2020 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-33214549

RESUMO

The liver plays a central role in metabolism, protein synthesis and detoxification. It possesses unique regenerative capacity upon injury. While many factors regulating cellular proliferation during liver repair have been identified, the mechanisms by which the injured liver maintains vital functions prior to tissue recovery are unknown. Here, we identify a new phase of functional compensation following acute liver injury that occurs prior to cellular proliferation. By coupling single-cell RNA-seq with in situ transcriptional analyses in two independent murine liver injury models, we discover adaptive reprogramming to ensure expression of both injury response and core liver function genes dependent on macrophage-derived WNT/ß-catenin signaling. Interestingly, transcriptional compensation is most prominent in non-proliferating cells, clearly delineating two temporally distinct phases of liver recovery. Overall, our work describes a mechanism by which the liver maintains essential physiological functions prior to cellular reconstitution and characterizes macrophage-derived WNT signals required for this compensation.

9.
Sci Rep ; 10(1): 18367, 2020 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-33110171

RESUMO

Medium-chain triglycerides (MCT), containing C8-C12 fatty acids, are used to treat several pediatric disorders and are widely consumed as a nutritional supplement. Here, we investigated the role of the sirtuin deacylase Sirt5 in MCT metabolism by feeding Sirt5 knockout mice (Sirt5KO) high-fat diets containing either C8/C10 fatty acids or coconut oil, which is rich in C12, for five weeks. Coconut oil, but not C8/C10 feeding, induced periportal macrovesicular steatosis in Sirt5KO mice. 14C-C12 degradation was significantly reduced in Sirt5KO liver. This decrease was localized to the mitochondrial ß-oxidation pathway, as Sirt5KO mice exhibited no change in peroxisomal C12 ß-oxidation. Endoplasmic reticulum ω-oxidation, a minor fatty acid degradation pathway known to be stimulated by C12 accumulation, was increased in Sirt5KO liver. Mice lacking another mitochondrial C12 oxidation enzyme, long-chain acyl-CoA dehydrogenase (LCAD), also developed periportal macrovesicular steatosis when fed coconut oil, confirming that defective mitochondrial C12 oxidation is sufficient to induce the steatosis phenotype. Sirt5KO liver exhibited normal LCAD activity but reduced mitochondrial acyl-CoA synthetase activity with C12. These studies reveal a role for Sirt5 in regulating the hepatic response to MCT and may shed light into the pathogenesis of periportal steatosis, a hallmark of human pediatric non-alcoholic fatty liver disease.

10.
Hepatology ; 2020 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-32794202

RESUMO

Constitutive androstane receptor (CAR) agonists, such as TCPOBOP, are known to cause robust hepatocyte proliferation and hepatomegaly in mice along with induction of drug metabolism genes, without any associated liver injury. Yes-associated protein (Yap) is a key transcription regulator that tightly controls organ size including that of liver. Ours and other previous studies suggested increased nuclear localization and activation of Yap after TCPOBOP-treatment in mice and potential role of Yap in CAR-driven proliferative response. Here, we investigated a direct role of Yap in CAR-driven hepatomegaly and hepatocyte proliferation using hepatocyte-specific Yap-KO mice. AAV8-TBG-CRE vector was injected to Yap-floxed mice for achieving hepatocyte-specific Yap deletion followed by TCPOBOP-treatment. Yap deletion did not decrease protein expression of CAR or CAR-driven induction of drug metabolism genes (including Cyp2b10, Cyp2c55 and Ugt1a1). However, Yap deletion substantially reduced TCPOBOP-induced hepatocyte proliferation. TCPOBOP-driven cell cycle activation was disrupted in Yap-KO mice due to delayed (and decreased) induction of cyclin D1 and higher expression of p21, resulting in decreased phosphorylation of retinoblastoma (Rb) protein. Further, induction of other cyclins, which are sequentially involved in progression through cell cycle (including cyclin E1, A2 and B1) and important mitotic regulators (such as aurora B kinase and polo-like kinase 1) was remarkably reduced in Yap-KO mice. Microarray analysis revealed that 26% of TCPOBOP-responsive genes mainly related to proliferation, but not to drug metabolism, were altered by Yap deletion. Yap regulated these proliferation genes via alerting expression of Myc and Foxm1, two critical transcriptional regulators of CAR-mediated hepatocyte proliferation. Conclusion: Our study revealed an important role of Yap signaling in CAR-driven hepatocyte proliferation; however, CAR-driven induction of drug metabolism genes was independent of Yap.

11.
Am J Pathol ; 190(10): 2080-2094, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32615075

RESUMO

Platelet-derived growth factor receptor (PDGFR)-α plays roles in cell survival, proliferation, and differentiation; however, its function in chronic liver injury sequelae, such as fibrosis, is unknown. Hepatic stellate cells (HSCs), the primary mediators of fibrosis, undergo activation, which entails differentiation to myofibroblasts, proliferation, migration, and collagen deposition, partially in response to PDGFs. To examine the role of PDGFR-α in HSCs, Lrat-Cre recombinase and Pdgfra-floxed mice were bred to generate Lrat-CrePdgfra-/- (knockout) animals, which were subjected to chronic liver injury through carbon tetrachloride treatment, bile duct ligation, and 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine. Although no major difference was observed after other types of liver injury, PDGFR-α loss in HSCs led to a significant albeit transient reduction in fibrosis after carbon tetrachloride injury, associated with increased HSC death and reduced migration. There was continued alleviation of hepatocellular injury in knockout mice despite ongoing carbon tetrachloride insult, associated with increased numbers of CD68 and F480 macrophages and increased clearance of damaged hepatocytes. Altogether our findings support a profibrotic role of PDGFR-α in HSCs during chronic liver injury in vivo via regulation of HSC survival and migration and affect the immune microenvironment, especially macrophages in clearing dying hepatocytes. Thus, our study provides a preclinical foundation for the future testing of therapeutic PDGFR-α inhibition in hepatic fibrosis, especially in combination with other therapies.


Assuntos
Carcinoma Hepatocelular/patologia , Células Estreladas do Fígado/metabolismo , Cirrose Hepática/patologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Animais , Tetracloreto de Carbono/metabolismo , Carcinoma Hepatocelular/metabolismo , Movimento Celular/fisiologia , Fígado/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos Knockout , Receptores Proteína Tirosina Quinases/metabolismo
12.
J Hepatol ; 73(5): 1013-1022, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32540177

RESUMO

BACKGROUND & AIMS: The heterodimeric integrin receptor α4ß7 regulates CD4 T cell recruitment to inflamed tissues, but its role in the pathogenesis of non-alcoholic steatohepatitis (NASH) is unknown. Herein, we examined the role of α4ß7-mediated recruitment of CD4 T cells to the intestine and liver in NASH. METHODS: Male littermate F11r+/+ (control) and junctional adhesion molecule A knockout F11r-/- mice were fed a normal diet or a western diet (WD) for 8 weeks. Liver and intestinal tissues were analyzed by histology, quantitative reverse transcription PCR (qRT-PCR), 16s rRNA sequencing and flow cytometry. Colonic mucosa-associated microbiota were analyzed using 16s rRNA sequencing. Liver biopsies from patients with NASH were analyzed by confocal imaging and qRT-PCR. RESULTS: WD-fed knockout mice developed NASH and had increased hepatic and intestinal α4ß7+ CD4 T cells relative to control mice who developed mild hepatic steatosis. The increase in α4ß7+ CD4 T cells was associated with markedly higher expression of the α4ß7 ligand mucosal addressin cell adhesion molecule 1 (MAdCAM-1) in the colonic mucosa and livers of WD-fed knockout mice. Elevated MAdCAM-1 expression correlated with increased mucosa-associated Proteobacteria in the WD-fed knockout mice. Antibiotics reduced MAdCAM-1 expression indicating that the diet-altered microbiota promoted colonic and hepatic MAdCAM-1 expression. α4ß7 blockade in WD-fed knockout mice significantly decreased α4ß7+ CD4 T cell recruitment to the intestine and liver, attenuated hepatic inflammation and fibrosis, and improved metabolic indices. MAdCAM-1 blockade also reduced hepatic inflammation and fibrosis in WD-fed knockout mice. Hepatic MAdCAM-1 expression was elevated in patients with NASH and correlated with higher expression of α4 and ß7 integrins. CONCLUSIONS: These findings establish α4ß7/MAdCAM-1 as a critical axis regulating NASH development through colonic and hepatic CD4 T cell recruitment. LAY SUMMARY: Non-alcoholic steatohepatitis (NASH) is an advanced and progressive form of non-alcoholic fatty liver disease (NAFLD), and despite its growing incidence no therapies currently exist to halt NAFLD progression. Herein, we show that blocking integrin receptor α4ß7-mediated recruitment of CD4 T cells to the intestine and liver not only attenuates hepatic inflammation and fibrosis, but also improves metabolic derangements associated with NASH. These findings provide evidence for the potential therapeutic application of α4ß7 antibody in the treatment of human NASH.

14.
J Cancer ; 11(15): 4614-4624, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32489479

RESUMO

Platelet-derived growth receptor α (PDGFRα) is a key factor in many pathophysiological processes. The expression level of PDGFRα is significantly elevated in the early stage of liver development and maintained at a lower level in adult normal livers. In this study, we constructed a liver-specific PDGFRαD842 mutant transgenic (TG) mice model to explore the effect of continuous activation of PDGFRα on liver regeneration and hepatocarcinogenesis. 14-day-old TG and wild-type (WT) mice were intraperitoneally injected with diethylnitrosamine (DEN) at a dose of 25 µg/g body weight. Two-month-old male TG and WT mice were subjected to partial hepatectomy (PH). The liver tissues were collected for further analysis at different time points. Overexpression of PDGFRα D842V and its target genes, Akt, c-myc and cyclin D1 in hepatocytes with no overt phenotype versus WT mice were compared. Unexpectedly, a dramatic decrease in hepatocyte proliferation was noted after PH in TG versus WT mice, possibly due to the downregulation of hepatocyte growth factor receptor (MET) and epidermal growth factor receptor (EGFR). No TG mice developed HCC spontaneously after 14 months follow-up. However, TG mice were more resistant to DEN-induced hapatocarcinogenesis at 6, 10, and 12 months of age, showing delayed hepatocyte proliferation and apoptosis, lower tumor incidence, smaller size and fewer number, compared with age-matched WTs, partially through downregulation of MET and EGFR. In conclusion, continuous activation of PDGFRα signaling by expression of PDGFRα D842V does not promote, but inhibit hepatic regeneration and hepatocarcinogenesis, possibly through compensatory downregulation of MET and EGFR.

15.
Gene Expr ; 20(2): 139-145, 2020 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-32503685

RESUMO

The incidence of hepatocellular cancer (HCC) is gradually rising. HCC occurs as a sequela to various chronic liver diseases and ensuing cirrhosis. There have been many therapies approved for unresectable HCC in the last 5 years, including immune checkpoint inhibitors, and the overall response rates have improved. However, there are many cases that do not respond, and personalized medicine is lacking, making HCC an unmet clinical need. Generation of appropriate animal models have been key to our understanding of HCC. Based on the overall concept of hepatocarcinogenesis, two major categories of animal models are discussed herein that can be useful to address specific questions. One category is described as the outside-in model of HCC and is based on the premise that it takes decades of hepatocyte injury, death, wound healing, and regeneration to eventually lead to DNA damage and mutations in a hepatocyte, which initiates tumorigenesis. Several animal models have been generated, which attempt to recapitulate this complex tissue damage and cellular interplay through genetics, diets, and toxins. The second category is the inside-out model of HCC, where clinically relevant genes can be coexpressed in a small subset of hepatocytes to yield a tumor, which matches HCC subsets in gene expression. This model has been made possible in part by the widely available molecular characterization of HCC, and in part by modalities like sleeping beauty transposon/transposase, Crispr/Cas9, and hydrodynamic tail vein injection. These two categories of HCC have distinct pros and cons, which are discussed in this Thinking Out Loud article.

16.
J Biol Chem ; 295(20): 7003-7017, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32273342

RESUMO

Cholelithiasis is one of the most prevalent gastroenterological diseases and is characterized by the formation of gallstones in the gallbladder. Both clinical and preclinical data indicate that obesity, along with comorbidity insulin resistance, is a predisposing factor for cholelithiasis. Forkhead box O1 (FoxO1) is a key transcription factor that integrates insulin signaling with hepatic metabolism and becomes deregulated in the insulin-resistant liver, contributing to dyslipidemia in obesity. To gain mechanistic insights into how insulin resistance is linked to cholelithiasis, here we determined FoxO1's role in bile acid homeostasis and its contribution to cholelithiasis. We hypothesized that hepatic FoxO1 deregulation links insulin resistance to impaired bile acid metabolism and cholelithiasis. To address this hypothesis, we used the FoxO1LoxP/LoxP-Albumin-Cre system to generate liver-specific FoxO1-knockout mice. FoxO1-knockout mice and age- and sex-matched WT littermates were fed a lithogenic diet, and bile acid metabolism and gallstone formation were assessed in these animals. We showed that FoxO1 affected bile acid homeostasis by regulating hepatic expression of key enzymes in bile acid synthesis and in biliary cholesterol and phospholipid secretion. Furthermore, FoxO1 inhibited hepatic expression of the bile acid receptor farnesoid X receptor and thereby counteracted hepatic farnesoid X receptor signaling. Nonetheless, hepatic FoxO1 depletion neither affected the onset of gallstone disease nor impacted the disease progression, as FoxO1-knockout and control mice of both sexes had similar gallstone weights and incidence rates. These results argue against the notion that FoxO1 is a link between insulin resistance and cholelithiasis.

17.
Epigenomics ; 12(5): 381-384, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32090611
19.
Cell Stem Cell ; 26(1): 2-3, 2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31951586

RESUMO

Despite minimal turnover, liver cells possess immense regenerative capacity. Some studies suggest existence of a hepatocyte subset with such unique capabilities. However, in the current issue of Cell Stem Cell, three independent studies (Chen et al., 2020; Matsumoto et al., 2020, and Sun et al., 2020) demonstrate an equitable homeostatic and reparative potential of all hepatocytes, irrespective of their lobular location or ploidy status.


Assuntos
Hepatócitos , Regeneração Hepática , Proliferação de Células , Homeostase , Humanos , Fígado , Poliploidia
20.
Am J Pathol ; 190(2): 372-387, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31843499

RESUMO

Aging is associated with inflammation and metabolic syndrome, which manifests in the liver as nonalcoholic fatty liver disease (NAFLD). NAFLD can range in severity from steatosis to fibrotic steatohepatitis and is a major cause of hepatic morbidity. However, the pathogenesis of NAFLD in naturally aged animals is unclear. Herein, we performed a comprehensive study of lipid content and inflammatory signature of livers in 19-month-old aged female mice. These animals exhibited increased body and liver weight, hepatic triglycerides, and inflammatory gene expression compared with 3-month-old young controls. The aged mice also had a significant increase in F4/80+ hepatic macrophages, which coexpressed CD11b, suggesting a circulating monocyte origin. A global knockout of the receptor for monocyte chemoattractant protein (CCR2) prevented excess steatosis and inflammation in aging livers but did not reduce the number of CD11b+ macrophages, suggesting changes in macrophage accumulation precede or are independent from chemokine (C-C motif) ligand-CCR2 signaling in the development of age-related NAFLD. RNA sequencing further elucidated complex changes in inflammatory and metabolic gene expression in the aging liver. In conclusion, we report a previously unknown accumulation of CD11b+ macrophages in aged livers with robust inflammatory and metabolic transcriptomic changes. A better understanding of the hallmarks of aging in the liver will be crucial in the development of preventive measures and treatments for end-stage liver disease in elderly patients.


Assuntos
Envelhecimento/patologia , Quimiocina CCL2/metabolismo , Modelos Animais de Doenças , Inflamação/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Receptores CCR2/metabolismo , Envelhecimento/metabolismo , Animais , Peso Corporal , Quimiocina CCL2/genética , Feminino , Perfilação da Expressão Gênica , Inflamação/etiologia , Inflamação/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Tamanho do Órgão , Receptores CCR2/genética
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