β-Catenin Links Hepatic Metabolic Zonation with Lipid Metabolism and Diet-Induced Obesity in Mice

Behari, Jaideep; Li, Huanan; Liu, Shiguang; Stefanović-Račić, Maja; Alonso, Laura; O’Donnell, Christopher P.; Shiva, Sruti; Singamsetty, Srikanth; Watanabe, Yoshio; Singh, Vijay; Liu, Qing

doi:10.1016/j.ajpath.2014.08.022

Cited by 52 publications

(62 citation statements)

References 36 publications

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“…There is a relatively limited number of conditions resulting in perturbed metabolic zonation in the absence of cirrhosis. Nonalcoholic fatty liver disease and hepatitis C infection in the early stages of the disease are among these conditions affecting liver zonation . However, there is no evidence that these conditions affect HNF‐4α expression …”

Section: Discussionmentioning

confidence: 99%

Down‐regulation of hepatocyte nuclear factor‐4α and defective zonation in livers expressing mutant Z α1‐antitrypsin

et al. 2017

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a 1 -Antitrypsin (AAT) deficiency is one of the most common genetic disorders and the liver disease due to the Z mutant of AAT (ATZ) is a prototype of conformational disorder due to protein misfolding with consequent aberrant intermolecular protein aggregation. In the present study, we found that livers of PiZ transgenic mice expressing human ATZ have altered expression of a network of hepatocyte transcriptional factors, including hepatocyte nuclear factor-4a, that is early down-regulated and induces a transcriptional repression of ATZ expression. Reduced hepatocyte nuclear factor-4a was associated with activation of b-catenin, which regulates liver zonation. Livers of PiZ mice and human patients with AAT deficiency were both found to have a severe perturbation of liver zonation. Functionally, PiZ mice showed a severe defect of ureagenesis, as shown by increased baseline ammonia, and reduced urea production and survival after an ammonia challenge. Down-regulation of hepatocyte nuclear factor-4a expression and defective zonation in livers have not been recognized so far as features of the liver disease caused by ATZ and are likely involved in metabolic disturbances and in the increased risk of hepatocellular carcinoma in patients with AAT deficiency. Conclusion: The findings of this study are consistent with the concept that abnormal AAT protein conformation and intrahepatic accumulation have broad effects on metabolic liver functions. (HEPATOLOGY 2017;66:124-135) a 1 -Antitrypsin (AAT) deficiency (AATD) is one of the most common genetic disorders. The Z deficiency allele (p.Glu342Lys) of the SERPINA1 gene is present in 1 in 25 of the north European Caucasian population, of whom 1 in 2,000 to 1 in 3,500 are homozygotes.(1) The Z mutation results in deficiency of the major circulating protease inhibitor AAT predisposing to early-onset panlobular basal emphysema. Concomitantly, it causes retention of the protein within hepatocytes that is associated with neonatal hepatitis, cirrhosis, and hepatocellular carcinoma (HCC).(1,2) The natural history of liver disease due to homozygous Z allele is highly variable, and approximately 20% of homozygous ZZ newborns develop symptomatic cholestatic hepatitis.(3) Approximately 50% of ZZ infants and children are likely to develop Abbreviations: AAT, a 1 -antitrypsin; AATD, AAT deficiency; ARG1, arginase 1; ATZ, AAT encoded by the Z allele; CDH1, cadherin-1;

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Section: Discussionmentioning

confidence: 99%

Down‐regulation of hepatocyte nuclear factor‐4α and defective zonation in livers expressing mutant Z α1‐antitrypsin

et al. 2017

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“…In a skeletal muscle cell line, Wnt stimulation was shown to increase the transcription of IRS1 , which is a direct transcriptional target of β-catenin [16]. β-catenin was also reported to regulate the establishment of hepatic metabolic zonation [17, 18]. These findings led us to study how hepatic β-catenin expression relates to steatohepatitis histology.…”

Section: Introductionmentioning

confidence: 99%

Hepatic IRS1 and ß-catenin expression is associated with histological progression and overt diabetes emergence in NAFLD patients

et al. 2018

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BackgroundNonalcoholic fatty liver disease (NAFLD) is a risk factor for type 2 diabetes. Our aim was to investigate the relationship between NAFLD and impaired glucose metabolism in terms of insulin receptor substrate 1 and 2 (IRS1 and IRS2) expression in the liver.MethodsLiver biopsy was performed at the University of Tokyo Hospital between November 2011 and March 2016 on 146 patients with NAFLD who were not being treated with any diabetes or dyslipidemia drugs. Among them, 63 underwent liver biopsy after an overnight fast, and 83 at 5 h after an oral glucose tolerance test (OGTT). Differences in messenger RNA (mRNA) levels of several glucose metabolism-related factors were determined and correlated with hepatic histological changes assessed by NAFLD activity score. We prospectively followed up with the patients until May 2017.ResultsHepatic necroinflammation was significantly correlated with serum insulin levels and inversely correlated with IRS1 mRNA levels. In specimens obtained after an OGTT, hepatic necroinflammation and IRS1 expression correlated significantly with both peripheral and hepatic insulin resistance. We also found that hepatic β-catenin and glucokinase mRNA levels were elevated in patients undergoing liver biopsy after an OGTT, especially in those with less hepatic necroinflammation and a lower degree of fibrosis. A prospective cohort study showed that ballooning is the most significant risk factor for developing diabetes.ConclusionsThe decreased hepatic expression of IRS1 and β-catenin in NAFLD is linked to histological progression such as ballooning, and might lead to diabetes as a result of impaired glucose metabolism.Electronic supplementary materialThe online version of this article (10.1007/s00535-018-1472-0) contains supplementary material, which is available to authorized users.

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“…36,37 Another recent study carefully assessed the involvement of b-catenin signaling in lipid metabolism in hepatocytes. 38 Hepatocyte-specific b-catenin knockout (KO) mice and hepatocyte-specific stable b-catenin expressing transgenic (TG) mice were fed HFDs. While chow-fed TG and KO mice had normal liver histology, in TG mice the obesogenic HFD led to notable pericentral steatosis with periportal sparing.…”

Section: Metabolic Zonation Nafld and Hccmentioning

confidence: 99%

Pre-clinical and clinical investigations of metabolic zonation in liver diseases: The potential of microphysiology systems

Soto-Gutiérrez

Gough

Vernetti

et al. 2017

Exp Biol Med (Maywood)

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The establishment of metabolic zonation within a hepatic lobule ascribes specific functions to hepatocytes based on unique, location-dependent gene expression patterns. Recently, there have been significant developments in the field of metabolic liver zonation. A little over a decade ago, the role of β-catenin signaling was identified as a key regulator of gene expression and function in pericentral hepatocytes. Since then, additional molecules have been identified that regulate the pattern of Wnt/β-catenin signaling within a lobule and determine gene expression and function in other hepatic zones. Currently, the molecular basis of metabolic zonation in the liver appears to be a ‘push and pull’ between signaling pathways. Such compartmentalization not only provides an efficient assembly line for hepatocyte functions but also can account for restricting the initial hepatic damage and pathology from some hepatotoxic drugs to specific zones, possibly enabling effective regeneration and restitution responses from unaffected cells. Careful analysis and experimentation have also revealed that many pathological conditions in the liver lobule are spatially heterogeneous. We will review current research efforts that have focused on examination of the role and regulation of such mechanisms of hepatocyte adaptation and repair. We will discuss how the pathological organ-specific microenvironment affects cell signaling and metabolic liver zonation, especially in steatosis, viral hepatitis, and hepatocellular carcinoma. We will discuss how the use of new human microphysiological platforms will lead to a better understanding of liver disease progression, diagnosis, and therapies. In conclusion, we aim to provide insights into the role and regulation of metabolic zonation and function using traditional and innovative approaches. Impact statement Liver zonation of oxygen tension along the liver sinusoids has been identified as a critical liver microenvironment that impacts specific liver functions such as intermediary metabolism of amino acids, lipids, and carbohydrates, detoxification of xenobiotics and as sites for initiation of liver diseases. To date, most information on the role of zonation in liver disease including, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC) have been obtained from animal models. It is now possible to complement animal studies with human liver, microphysiology systems (MPS) containing induced pluripotent stem cells engineered to create disease models where it is also possible to control the in vitro liver oxygen microenvironment to define the role of zonation on the mechanism(s) of disease progression. The field now has the tools to investigate human liver disease progression, diagnosis, and therapeutic development.

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β-Catenin Links Hepatic Metabolic Zonation with Lipid Metabolism and Diet-Induced Obesity in Mice

Cited by 52 publications

References 36 publications

Down‐regulation of hepatocyte nuclear factor‐4α and defective zonation in livers expressing mutant Z α1‐antitrypsin

Down‐regulation of hepatocyte nuclear factor‐4α and defective zonation in livers expressing mutant Z α1‐antitrypsin

Hepatic IRS1 and ß-catenin expression is associated with histological progression and overt diabetes emergence in NAFLD patients

Pre-clinical and clinical investigations of metabolic zonation in liver diseases: The potential of microphysiology systems

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