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Hepatic Polarization Accelerated by Mechanical Compaction Involves HNF4? Activation.

ABSTRACT: There remain few data about the role of homeostatic compaction in hepatic polarization. A previous study has found that mechanical compaction can accelerate hepatocyte polarization; however, the cellular mechanism underlying the effect is mostly unclear. Hepatocyte nuclear factor 4 alpha (HNF4?) is crucial for hepatic polarization in liver morphogenesis. Therefore, we sought to identify any possible involvement of HNF4? in the process of hepatocyte polarization accelerated by mechanical compaction. We first verified in the nonhepatic cell model HEK-293T, and the hepatic cell model primary hepatocytes that the mechanical compaction on cell aggregates simulated by using transient centrifugation can directly activate the expression of HNF4? promoters. Moreover, data using primary hepatocytes showed that the HNF4? expression is positively associated with the levels of compaction force: 2.1-folds higher at the mRNA level and 2.1-folds higher at the protein level for 500?g vs. 0?g. Furthermore, activated HNF4? expression is associated with the enhanced biliary canalicular formation and the increased production of albumin and urea. Pretreatment with Latrunculin B, an inhibitor of F-actin, and SHE78-7, an inhibitor of E-cadherin, which both interrupt the pathway of mechanical transduction, partially but significantly reduced the HNF4? expression and production of albumin and urea. In conclusion, HNF4? can be actively involved in the hepatic polarization in the context of environmental mechanical compaction.

SUBMITTER: Yang J

PROVIDER: S-EPMC7426769 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Hepatic Polarization Accelerated by Mechanical Compaction Involves HNF4α Activation.

Yang Jinlian J Liang Jiaen J Zheng Yongjian Y Li Shiying S Li Yang Y Liu Haiyan H Chen Guanzhong G Ma Jing J Liao Ziyu Z Lin Jiezhao J Jiang Zesheng Z Wang Yan Y

BioMed research international 20200805

There remain few data about the role of homeostatic compaction in hepatic polarization. A previous study has found that mechanical compaction can accelerate hepatocyte polarization; however, the cellular mechanism underlying the effect is mostly unclear. Hepatocyte nuclear factor 4 alpha (HNF4α) is crucial for hepatic polarization in liver morphogenesis. Therefore, we sought to identify any possible involvement of HNF4α in the process of hepatocyte polarization accelerated by mecha ...[more]

PMID: 32802875

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Project description:Background & aimsAlpha-1 antitrypsin deficiency is caused by mutations in SERPINA1, most commonly homozygosity for the Pi∗Z variant, and can present as liver disease. While heterozygosity for Pi∗Z (Pi∗MZ) is linked to increased risk of cirrhosis, whether the Pi∗MZ genotype is associated with an increased rate of decompensation among patients who already have compensated cirrhosis is not known.MethodsThis was a retrospective study of Michigan Genomics Initiative participants with baseline compensated cirrhosis. The primary predictors were Pi∗MZ or Pi∗MS genotype (vs. Pi∗MM). The primary outcomes were hepatic decompensation with ascites, hepatic encephalopathy, or variceal bleeding, or the combined endpoint of liver-related death or liver transplant, both modeled with Fine-Gray competing risk models.ResultsWe included 576 patients with baseline compensated cirrhosis who had undergone genotyping, of whom 474 had Pi∗MM, 49 had Pi∗MZ, and 52 had Pi∗MS genotypes. Compared to Pi∗MM genotype, Pi∗MZ was associated with increased rates of hepatic decompensation (hazard ratio 1.81; 95% CI 1.22-2.69; p = 0.003) and liver transplant or liver-related death (hazard ratio 2.07; 95% CI 1.21-3.52; p = 0.078). These associations remained significant after adjustment for severity of underlying liver disease, and were robust across subgroup analyses based on etiology, sex, obesity, and diabetes status. Pi∗MS was not associated with decompensation or death/transplantation.ConclusionsThe SERPINA1 Pi∗MZ genotype is associated with an increased rate of hepatic decompensation and decreased transplant-free survival among patients with baseline compensated cirrhosis.Lay summaryThere is a mutation in the gene SERPINA1 called Pi∗MZ which increases risk of liver scarring (cirrhosis); however, it is not known what effect Pi∗MZ has if someone already has cirrhosis. In this study, we found that people who had cirrhosis and Pi∗MZ developed complications from cirrhosis faster than those who did not have the mutation.

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Hepatic Polarization Accelerated by Mechanical Compaction Involves HNF4? Activation.

Publications

Hepatic Polarization Accelerated by Mechanical Compaction Involves HNF4<i>α</i> Activation.

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