WW domain-binding protein 2 overexpression prevents diet-induced liver steatosis and insulin resistance through AMPKβ1.
Cell death & disease
Nonalcoholic fatty liver disease (NAFLD) is prevalent clinically and can lead to more serious chronic liver disease. However, the pathological mechanism is still unclear, and thus, there are no approved drugs on the market. Transcriptional coactivator WW domain-binding protein 2 (WBP2) is a newly discovered oncogene that has an important relationship with the occurrence and development of breast cancer and mediates the interaction between Wnt and various other signaling pathways. The expression level of WBP2 was decreased in NAFLD. Overexpression of WBP2 with AAV in vivo alleviated liver fat deposition and insulin resistance induced by a high-fat diet (HFD). Knockdown of WBP2 with AAV aggravated HFD-induced fatty liver and insulin resistance. In vitro experiments showed that in the human normal hepatocyte cell line LO2 and primary hepatocytes isolated from mice, overexpression of WBP2 reduced fat deposition, and knocking out or knocking down WBP2 aggravated PA-induced fat deposition. Through mass spectrometry, we found that WBP2 can bind to AMPKβ1, and by mutating AMPKβ1, we found that WBP2 can induce phosphorylation of AMPKβ1 at S108 and then activate the AMPK pathway to affect lipid metabolism. The effect of WBP2 on NAFLD provides a possible new direction for future research on NAFLD.
10.1038/s41419-021-03536-8
WISP1 is a novel adipokine linked to inflammation in obesity.
Murahovschi Veronica,Pivovarova Olga,Ilkavets Iryna,Dmitrieva Renata M,Döcke Stephanie,Keyhani-Nejad Farnaz,Gögebakan Özlem,Osterhoff Martin,Kemper Margrit,Hornemann Silke,Markova Mariya,Klöting Nora,Stockmann Martin,Weickert Martin O,Lamounier-Zepter Valeria,Neuhaus Peter,Konradi Alexandra,Dooley Steven,von Loeffelholz Christian,Blüher Matthias,Pfeiffer Andreas F H,Rudovich Natalia
Diabetes
WISP1 (Wnt1-inducible signaling pathway protein-1, also known as CCN4) is a member of the secreted extracellular matrix-associated proteins of the CCN family and a target gene of the Wingless-type (WNT) signaling pathway. Growing evidence links the WNT signaling pathway to the regulation of adipogenesis and low-grade inflammation in obesity. We aimed to validate WISP1 as a novel adipokine. Human adipocyte differentiation was associated with increased WISP1 expression and secretion. Stimulation of human macrophages with WISP1 led to a proinflammatory response. Circulating WISP1 and WISP1 subcutaneous adipose tissue expression were regulated by weight changes in humans and mice. WISP1 expression in visceral and subcutaneous fat tissue was associated with markers of insulin resistance and inflammation in glucose-tolerant subjects. In patients with nonalcoholic fatty liver disease, we found no correlation among disease activity score, liver fat content, and WISP1 expression. Insulin regulated WISP1 expression in adipocytes in vitro but had no acute effect on WISP1 gene expression in subcutaneous fat tissue in overweight subjects who had undergone hyperinsulinemic clamp experiments. The data suggest that WISP1 may play a role in linking obesity to inflammation and insulin resistance and could be a novel therapeutic target for obesity.
10.2337/db14-0444
MicroRNA deregulation in nonalcoholic steatohepatitis-associated liver carcinogenesis.
de Conti Aline,Ortega Juliana Festa,Tryndyak Volodymyr,Dreval Kostiantyn,Moreno Fernando Salvador,Rusyn Ivan,Beland Frederick A,Pogribny Igor P
Oncotarget
Hepatocellular carcinoma (HCC) is the fastest-rising cause of cancer-related death in the United States. Recent epidemiological studies have identified nonalcoholic steatohepatitis (NASH), a progressive form of nonalcoholic fatty liver disease (NAFLD), as a major risk factor for HCC. Elucidating the underlying mechanisms associated with the development of NASH-derived HCC is critical for identifying early biomarkers for the progression of the disease and for treatment and prevention. In the present study, using liver samples from C57BL/6J mice submitted to the Stelic Animal Model (STAM) of NASH-associated liver carcinogenesis, we investigated the role of microRNA (miRNA) alterations in the pathogenesis of NASH-derived HCC. We found substantial alterations in the expression of miRNAs, with the greatest number occurring in full-fledged HCC. Mechanistically, altered miRNA expression was associated with activation of major hepatocarcinogenesis-related pathways, including the TGF-β, Wnt/β-catenin, ERK1/2, mTOR, and EGF signaling. In addition, the over-expression of the miR-221-3p and miR-222-3p and oncogenic miR-106b∼25 cluster was accompanied by the reduced protein levels of their targets, including E2F transcription factor 1 (E2F1), phosphatase and tensin homolog (PTEN), and cyclin-dependent kinase inhibitor 1 (CDKN1A). Importantly, miR-93-5p, miR-221-3p, and miR-222-3p were also significantly over-expressed in human HCC. These findings suggest that aberrant expression of miRNAs may have mechanistic significance in NASH-associated liver carcinogenesis and may serve as an indicator for the development of NASH-derived HCC.
10.18632/oncotarget.19774
Targeting the Wnt signaling pathway: the challenge of reducing scarring without affecting repair.
Jarman Edward J,Boulter Luke
Expert opinion on investigational drugs
: Globally, deaths from liver disease are increasing and for most patients there are few curative options. Fibrosis or scarring is often associated with the formation and progression of liver disease; however, clinical anti-fibrotic therapies are lacking. Recent work has shown that Wnt signaling, a signaling pathway that is necessary for embryonic development and cancer, can also regulate scar formation in the liver.: This article seeks to shed light on the dualistic role of Wnt signaling in liver regeneration following injury and how Wnt signaling can regulate scar formation. It also discusses how Wnt signaling cooperates with other classical fibrogenic signaling cascades, such as TGFβ signaling. Finally, the article examines recent advances in the development of Wnt signaling pathway inhibitors and asks whether repurposing these agents as anti-fibrotic therapies is a realistic option.: The understanding of Wnt signaling in liver regeneration and fibrosis is in its infancy and whilst new generations of Wnt pathway inhibitors have shown anti-fibrotic effects, further research is necessary to enhance our understanding of the Wnt-landscape in different patterns of liver disease. This will accelerate the development of more specific Wnt inhibitor-based anti-fibrotics.
10.1080/13543784.2020.1718105
[Carcinoembryonic type specific markers and liver cancer immunotherapy].
Yao M,Yang J L,Wang L,Yao D F
Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology
Hepatocellular carcinoma (HCC) is a chronic inflammation derived from the background of hepatitis B and C virus (HBV and HCV) infection, chemical intoxicants, or non-alcoholic fatty liver disease. Cancerous liver cells can express and secrete a variety of relatively specific markers, such as carcinoembryonic type of alpha-fetoprotein (AFP), phosphatidylinositol-3 (Glypican-3, GPC-3), Wnt/β-Catenin key molecule of signaling pathway Wnt3a and liver cancer specific GGT-II (HS-GGT), etc. Clinical analysis of carcinoembryonic markers not only contributes to diagnosis and prognosis of HCC, but may also be the target of HCC immunotherapy with a promising prospect of development and application. This article reviews the latest valuable advances in carcinoembryonic type specific molecular markers and liver cancer immunotherapy.
10.3760/cma.j.cn501113-20200311-00107
Upregulation of non-canonical Wnt ligands and oxidative glucose metabolism in NASH induced by methionine-choline deficient diet.
Zhu Lixin,Baker Susan S,Shahein Abdul,Choudhury Shelly,Liu Wensheng,Bhatia Tavleen,Baker Robert D,Lee Techung
Trends in cell & molecular biology
Wnt ligands regulate metabolic pathways, and dysregulation of Wnt signaling contributes to chronic inflammatory disease. A knowledge gap exists concerning the role of aberrant Wnt signaling in non-alcoholic steatohepatitis (NASH), which exhibits metabolic syndrome and inflammation. Using a mouse model of methionine-choline deficient diet (MCDD)-induced NASH, we investigated the Wnt signaling pathways in relation to hepatic glucose oxidation. Mice fed the MCD diet for 6 weeks developed prominent NASH marked by macrovesicular steatosis, inflammation and lipid peroxidation. qPCR analysis reveals differential hepatic expression of canonical and non-canonical Wnt ligands. While expression of Wnt3a was decreased in NASH vs chow diet control, expression of Wnt5a and Wnt11 were increased 3 fold and 15 fold, respectively. Consistent with activation of non-canonical Wnt signaling, expression of the alternative Wnt receptor ROR2 was increased 5 fold with no change in LRP6 expression. Activities of the metabolic enzymes glucokinase, phosphoglucoisomerase, glyceraldehyde-3-phosphate dehydrogenase, pyruvate kinase, and pyruvate dehydrogenase were all elevated by MCDD. NASH-driven glucose oxidation was accompanied by a 6-fold increase in lactate dehydrogenase (LDH)-B with no change in LDH-A. In addition, glucose-6-phosphate dehydrogenase, the regulatory and NADPH-producing enzyme of the pentose phosphate pathway, was elevated in NASH. These data support a role of accelerated glucose oxidation in the development of NASH, which may be driven by non-canonical Wnt signaling.
The combined hyperlipidemia caused by impaired Wnt-LRP6 signaling is reversed by Wnt3a rescue.
Go Gwang-Woong,Srivastava Roshni,Hernandez-Ono Antonio,Gang Gyoungok,Smith Stephen B,Booth Carmen J,Ginsberg Henry N,Mani Arya
Cell metabolism
The underlying molecular genetic basis of combined hyperlipidemia, the most common atherogenic lipid disorder, is poorly characterized. Rare, nonconservative mutations in the Wnt coreceptor, LRP6, underlie autosomal dominant atherosclerosis, combined hyperlipidemia, and fatty liver disease. Mice with LRP6(R611C) mutation similarly developed elevated plasma LDL and TG levels and fatty liver. Further investigation showed that LRP6(R611C) mutation triggers hepatic de novo lipogenesis, lipid and cholesterol biosynthesis, and apoB secretion by an Sp1-dependent activation of IGF1, AKT, and both mTORC1 and mTORC2. These pathways were normalized after in vitro treatment of primary hepatocytes from LRP6(R611C) mice with either the IGF1R antagonist PPP, rapamycin, or rmWnt3a. Strikingly, in vivo administration of rmWnt3a to LRP6(R611C) mice normalized the altered expression of enzymes of DNL and cholesterol biosynthesis, and restored plasma TG and LDL levels to normal. These findings identify Wnt signaling as a regulator of plasma lipids and a target for treatment of hyperlipidemia.
10.1016/j.cmet.2013.11.023
How do mechanisms of hepatocarcinogenesis (HBV, HCV, and NASH) affect our understanding and approach to HCC?
American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting
The major etiologic factors for hepatocellular carcinoma (HCC), including chronic hepatitis B and C virus infections and nonalcoholic fatty liver disease, are now well established by epidemiologic investigations. The mechanisms by which these factors result in HCC have been extensively investigated but have not, to date, resulted in the development of specific therapeutic interventions. Other frequently occurring dysregulated pathways, including the Wnt/β-catenin signaling pathway, are proving difficult to target, but there are early suggestions that patients with "MET-high" HCC may benefit from the c-MET inhibitor tivantinib. Chronic inflammation and consequent cell damage and regenerative proliferation are common to all etiologic factors, and emerging evidence suggests that anti-inflammatory agents such as aspirin deserve further investigation as preventive agents.
10.1200/EdBook_AM.2013.33.e132
Wnt signaling, de novo lipogenesis, adipogenesis and ectopic fat.
Song Kangxing,Wang Shuxia,Mani Mitra,Mani Arya
Oncotarget
Wnt signaling is as a major regulator of adipogenesis. It differentially regulates the fate of mesenchymal stem cells (MSC) by promoting osteogenesis and myogenesis, and inhibiting adipogenesis[1]. Its loss of function has been associated with impaired osteogenesis[2] and diverse congenital and adult cardiovascular disorders[3,4]. Our group has identified loss of function mutations in Wnt coreceptor LRP6 that underlie autosomal dominant early onset coronary artery (CAD), osteoporosis and most features of the metabolic syndrome, including high plasma triglyceride and LDL-C, diabetes, hypertension, hyperuricemia and fatty liver disease (unpublished data). Following we will describe our most pertinent findings related to Wnt/LRP6 regulation of de novo lipogenesis and adipogenesis and the role of impaired Wnt signaling in generation of ectopic fat, insulin resistance, elevated plasma lipids and non-alcoholic fatty liver disease (NAFLD).
10.18632/oncotarget.2769
Maladaptive regeneration - the reawakening of developmental pathways in NASH and fibrosis.
Zhu Changyu,Tabas Ira,Schwabe Robert F,Pajvani Utpal B
Nature reviews. Gastroenterology & hepatology
With the rapid expansion of the obesity epidemic, nonalcoholic fatty liver disease is now the most common chronic liver disease, with almost 25% global prevalence. Nonalcoholic fatty liver disease ranges in severity from simple steatosis, a benign 'pre-disease' state, to the liver injury and inflammation that characterize nonalcoholic steatohepatitis (NASH), which in turn predisposes individuals to liver fibrosis. Fibrosis is the major determinant of clinical outcomes in patients with NASH and is associated with increased risks of cirrhosis and hepatocellular carcinoma. NASH has no approved therapies, and liver fibrosis shows poor response to existing pharmacotherapy, in part due to an incomplete understanding of the underlying pathophysiology. Patient and mouse data have shown that NASH is associated with the activation of developmental pathways: Notch, Hedgehog and Hippo-YAP-TAZ. Although these evolutionarily conserved fundamental signals are known to determine liver morphogenesis during development, new data have shown a coordinated and causal role for these pathways in the liver injury response, which becomes maladaptive during obesity-associated chronic liver disease. In this Review, we discuss the aetiology of this reactivation of developmental pathways and review the cell-autonomous and cell-non-autonomous mechanisms by which developmental pathways influence disease progression. Finally, we discuss the potential prognostic and therapeutic implications of these data for NASH and liver fibrosis.
10.1038/s41575-020-00365-6
Garlic-derived compound -allylmercaptocysteine inhibits hepatocarcinogenesis through targeting LRP6/Wnt pathway.
Xiao Jia,Xing Feiyue,Liu Yingxia,Lv Yi,Wang Xiaogang,Ling Ming-Tat,Gao Hao,Ouyang Songying,Yang Min,Zhu Jiang,Xia Yu,So Kwok-Fai,Tipoe George L
Acta pharmaceutica Sinica. B
Whether and how garlic-derived -allylmercaptocysteine (SAMC) inhibits hepatocellular carcinoma (HCC) is largely unknown. In the current study, the role of low-density lipoprotein receptor (LDLR)-related protein 6 (LRP6) in HCC progression and the anti-HCC mechanism of SAMC was examined in clinical sample, cell model and xenograft/orthotopic mouse models. We demonstrated that SAMC inhibited cell proliferation and tumorigenesis, while induced apoptosis of human HCC cells without influencing normal hepatocytes. SAMC directly interacted with Wnt-pathway co-receptor LRP6 on the cell membrane. LRP6 was frequently over-expressed in the tumor tissue of human HCC patients (66.7% of 48 patients) and its over-expression only correlated with the over-expression of -catenin, but not with age, gender, tumor size, stage and metastasis. Deficiency or over-expression of LRP6 in hepatoma cells could partly mimic or counteract the anti-tumor properties of SAMC, respectively. administration of SAMC significantly suppressed the growth of Huh-7 xenograft/orthotopic HCC tumor without causing undesirable side effects. In addition, stable down-regulation of LRP6 in Huh-7 facilitated the anti-HCC effects of SAMC. In conclusion, LRP6 can be a potential therapeutic target of HCC. SAMC is a promising specific anti-tumor agent for treating HCC subtypes with Wnt activation at the hepatoma cell surface.
10.1016/j.apsb.2017.10.003
MiR-146a-5p suppresses activation and proliferation of hepatic stellate cells in nonalcoholic fibrosing steatohepatitis through directly targeting Wnt1 and Wnt5a.
Du Jinghua,Niu Xuemin,Wang Yang,Kong Lingbo,Wang Rongqi,Zhang Yuguo,Zhao Suxian,Nan Yuemin
Scientific reports
Nonalcoholic fibrosing steatohepatitis is a uniform process throughout nonalcoholic fatty liver disease (NAFLD). MicroRNAs (miRNAs) have been suggested to modulate cellular processes in liver diseases. However, the functional role of miRNAs in nonalcoholic fibrosing steatohepatitis is largely unclear. In this study, we systematically analyzed the hepatic miRNAs by microarray analysis in nonalcoholic fibrosing steatohepatitis in C57BL/6J mice induced by methionine-choline deficient (MCD) diet. We identified 19 up-regulated and 18 down-regulated miRNAs in liver with fibrosis. Among these dysregulated miRNAs, miR-146a-5p was the most significant down-regulated miRNA. Luciferase activity assay confirmed that Wnt1 and Wnt5a were both the target genes of miR-146a-5p. Hepatic miR-146a-5p was down-regulated in fibrosing steatohepatitis, but its target genes Wnt1 and Wnt5a and their consequent effectors α-SMA and Col-1 were significantly up-regulated. In addition, miR-146a-5p was downregulated, whilst Wnt1 and Wnt5a were up-regulated in the activated primary hepatic stellate cells (HSCs) compared to the quiescent primary HSCs. Overexpression of miR-146a-5p in HSCs inhibited HSC activation and proliferation, which concomitant with the decreased expressions of Wnt1, Wnt5a, α-SMA and Col-1. In conclusion, miR-146a-5p suppresses activation and proliferation of HSCs in the progress of nonalcoholic fibrosing steatohepatitis through targeting Wnt1 and Wnt5a and consequent effectors α-SMA and Col-1.
10.1038/srep16163
Interrelationship of canonical and non-canonical Wnt signalling pathways in chronic metabolic diseases.
Ackers Ian,Malgor Ramiro
Diabetes & vascular disease research
Chronic diseases account for approximately 45% of all deaths in developed countries and are particularly prevalent in countries with the most sophisticated and robust public health systems. Chronic metabolic diseases, specifically lifestyle-related diseases pertaining to diet and exercise, continue to be difficult to treat clinically. The most prevalent of these chronic metabolic diseases include obesity, diabetes, non-alcoholic fatty liver disease, chronic kidney disease and cardiovascular disease and will be the focus of this review. Wnt proteins are highly conserved glycoproteins best known for their role in development and homeostasis of tissues. Given the importance of Wnt signalling in homeostasis, aberrant Wnt signalling likely regulates metabolic processes and may contribute to the development of chronic metabolic diseases. Expression of Wnt proteins and dysfunctional Wnt signalling has been reported in multiple chronic diseases. It is interesting to speculate about an interrelationship between the Wnt signalling pathways as a potential pathological mechanism in chronic metabolic diseases. The aim of this review is to summarize reported findings on the contrasting roles of Wnt signalling in lifestyle-related chronic metabolic diseases; specifically, the contribution of Wnt signalling to lipid accumulation, fibrosis and chronic low-grade inflammation.
10.1177/1479164117738442
Targeting the Wnt signaling pathway through R-spondin 3 identifies an anti-fibrosis treatment strategy for multiple organs.
Zhang Mingjun,Haughey Michael,Wang Nai-Yu,Blease Kate,Kapoun Ann M,Couto Suzana,Belka Igor,Hoey Timothy,Groza Matthew,Hartke James,Bennett Brydon,Cain Jennifer,Gurney Austin,Benish Brent,Castiglioni Paola,Drew Clifton,Lachowicz Jean,Carayannopoulos Leon,Nathan Steven D,Distler Jorg,Brenner David A,Hariharan Kandasamy,Cho Ho,Xie Weilin
PloS one
The Wnt/β-catenin signaling pathway has been implicated in human proliferative diseases such as cancer and fibrosis. The functions of β-catenin and several other components of this pathway have been investigated in fibrosis. However, the potential role of R-spondin proteins (RSPOs), enhancers of the Wnt/β-catenin signaling, has not been described. A specific interventional strategy targeting this pathway for fibrosis remains to be defined. We developed monoclonal antibodies against members of the RSPO family (RSPO1, 2, and 3) and probed their potential function in fibrosis in vivo. We demonstrated that RSPO3 plays a critical role in the development of fibrosis in multiple organs. Specifically, an anti-RSPO3 antibody, OMP-131R10, when dosed therapeutically, attenuated fibrosis in carbon tetrachloride (CCl4)-induced liver fibrosis, bleomycin-induced pulmonary and skin fibrosis models. Mechanistically, we showed that RSPO3 induces multiple pro-fibrotic chemokines and cytokines in Kupffer cells and hepatocytes. We found that the anti-fibrotic activity of OMP-131R10 is associated with its inhibition of β-catenin activation in vivo. Finally, RSPO3 was found to be highly elevated in the active lesions of fibrotic tissues in mouse models of fibrosis and in patients with idiopathic pulmonary fibrosis (IPF) and nonalcoholic steatohepatitis (NASH). Together these data provide an anti-fibrotic strategy for targeting the Wnt/β-catenin pathway through RSPO3 blockade and support that OMP-131R10 could be an important therapeutic agent for fibrosis.
10.1371/journal.pone.0229445
Characterization of hepatocellular carcinoma related genes and metabolites in human nonalcoholic fatty liver disease.
Digestive diseases and sciences
BACKGROUND:The worldwide prevalences of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are estimated to range from 30 to 40 % and 5-17 %, respectively. Hepatocellular carcinoma (HCC) is primarily caused by hepatitis B infection, but retrospective data suggest that 4-29 % of NASH cases will progress to HCC. Currently the connection between NASH and HCC is unclear. AIMS:The purpose of this study was to identify changes in expression of HCC-related genes and metabolite profiles in NAFLD progression. METHODS:Transcriptomic and metabolomic datasets from human liver tissue representing NAFLD progression (normal, steatosis, NASH) were utilized and compared to published data for HCC. RESULTS:Genes involved in Wnt signaling were downregulated in NASH but have been reported to be upregulated in HCC. Extracellular matrix/angiogenesis genes were upregulated in NASH, similar to reports in HCC. Iron homeostasis is known to be perturbed in HCC and we observed downregulation of genes in this pathway. In the metabolomics analysis of hepatic NAFLD samples, several changes were opposite to what has been reported in plasma of HCC patients (lysine, phenylalanine, citrulline, creatine, creatinine, glycodeoxycholic acid, inosine, and alpha-ketoglutarate). In contrast, multiple acyl-lyso-phosphatidylcholine metabolites were downregulated in NASH livers, consistent with observations in HCC patient plasma. CONCLUSIONS:These data indicate an overlap in the pathogenesis of NAFLD and HCC where several classes of HCC related genes and metabolites are altered in NAFLD. Importantly, Wnt signaling and several metabolites are different, thus implicating these genes and metabolites as mediators in the transition from NASH to HCC.
10.1007/s10620-013-2873-9
Heme Oxygenase-1 Suppresses Wnt Signaling Pathway in Nonalcoholic Steatohepatitis-Related Liver Fibrosis.
BioMed research international
METHODS:Mice were fed with a methionine-choline-deficient (MCD) diet for 8 weeks to induce steatohepatitis-related liver fibrosis and were treated with HO-1 inducer Hemin and inhibitor ZnPP. Mouse sera were collected for the biochemical analysis, and livers were obtained for further histological observation and gene expression analysis. HSC-T6 cells were cultured for the study and were administrated with Hemin and si-HO-1 to induce or inhibit the expression of HO-1. qPCR and Western blot were used to assess the mRNA and protein levels of genes. RESULTS:MCD-fed mice developed marked macrovesicular steatosis, focal necrosis, and inflammatory infiltration and pericellular fibrosis in liver sections. Administration of Hemin could significantly ameliorate the severity of steatosis, inflammation, and fibrosis and also could decrease the serum ALT and AST. We demonstrated that HO-1 induction was able to downregulate the key regulator of the canonical Wnt pathway Wnt1 and the noncanonical Wnt pathway Wnt5a. The downstream factors of the Wnt pathway -catenin and NFAT5 were inhibited by Hemin, but GSK-3 was upregulated compared to the MCD group, which were consistent with the study. Hemin markedly inhibited the TGF-1/Smad signaling pathway in both and studies. CONCLUSION:Our study demonstrated that HO-1 inhibited the activation of canonical and noncanonical Wnt signaling pathways in NASH-related liver fibrosis. Thus, these results may suggest a new therapeutic strategy for NASH-related liver fibrosis.
10.1155/2020/4910601
Aortic carboxypeptidase-like protein, a WNT ligand, exacerbates nonalcoholic steatohepatitis.
Teratani Toshiaki,Tomita Kengo,Suzuki Takahiro,Furuhashi Hirotaka,Irie Rie,Nishikawa Makoto,Yamamoto Junji,Hibi Toshifumi,Miura Soichiro,Minamino Tohru,Oike Yuichi,Hokari Ryota,Kanai Takanori
The Journal of clinical investigation
Incidence of nonalcoholic steatohepatitis (NASH), which is considered a hepatic manifestation of metabolic syndrome, has been increasing worldwide with the rise in obesity; however, its pathological mechanism is poorly understood. Here, we demonstrate that the hepatic expression of aortic carboxypeptidase-like protein (ACLP), a glycosylated, secreted protein, increases in NASH in humans and mice. Furthermore, we elucidate that ACLP is a ligand, unrelated to WNT proteins, that activates the canonical WNT pathway and exacerbates NASH pathology. In the liver, ACLP is specifically expressed in hepatic stellate cells (HSCs). As fatty liver disease progresses, ACLP expression is enhanced via activation of STAT3 signaling by obesity-related factors in serum. ACLP specifically binds to frizzled-8 and low-density lipoprotein-related receptor 6 to form a ternary complex that activates canonical WNT signaling. Consequently, ACLP activates HSCs by inhibiting PPARγ signals. HSC-specific ACLP deficiency inhibits fibrosis progression in NASH by inhibiting canonical WNT signaling in HSCs. The present study elucidates the role of canonical WNT pathway activation by ACLP in NASH pathology, indicating that NASH can be treated by targeting ACLP-induced canonical WNT pathway activation in HSCs.
10.1172/JCI92863
Epigenetic Activation of Wnt/β-Catenin Signaling in NAFLD-Associated Hepatocarcinogenesis.
Tian Yuan,Mok Myth T S,Yang Pengyuan,Cheng Alfred S L
Cancers
Non-alcoholic fatty liver disease (NAFLD), characterized by fat accumulation in liver, is closely associated with central obesity, over-nutrition and other features of metabolic syndrome, which elevate the risk of developing hepatocellular carcinoma (HCC). The Wnt/β-catenin signaling pathway plays a significant role in the physiology and pathology of liver. Up to half of HCC patients have activation of Wnt/β-catenin signaling. However, the mutation frequencies of CTNNB1 (encoding β-catenin protein) or other antagonists targeting Wnt/β-catenin signaling are low in HCC patients, suggesting that genetic mutations are not the major factor driving abnormal β-catenin activities in HCC. Emerging evidence has demonstrated that obesity-induced metabolic pathways can deregulate chromatin modifiers such as histone deacetylase 8 to trigger undesired global epigenetic changes, thereby modifying gene expression program which contributes to oncogenic signaling. This review focuses on the aberrant epigenetic activation of Wnt/β-catenin in the development of NAFLD-associated HCC. A deeper understanding of the molecular mechanisms underlying such deregulation may shed light on the identification of novel druggable epigenetic targets for the prevention and/or treatment of HCC in obese and diabetic patients.
10.3390/cancers8080076