Abstract
Background: Krüppel-like factor 6 (KLF6) is a ubiquitously expressed, multifunctional transcription factor and tumor suppressor gene. In previous studies, we identified KLF6 as an important transcription factor in hepatocyte glucose and lipid homeostasis, and downregulation of KLF6 was associated with accelerated tumor-growth of hepatocellular cancer. So far, no data is available on the role of KLF6 in acute liver injury and regeneration. Here, we aimed to investigate the expression pattern of hepatocyte KLF6 in patients with acute liver failure (ALF), in a human ex-vivo perfusion model of acetaminophen induced liver injury and to study the effects of hepatocyte specific KLF6 depletion in mice undergoing partial hepatectomy (PHx). Methods: Liver samples from 10 patients with drug-induced ALF were obtained (either liver biopsy or explanted liver in patients who underwent liver transplantation) and KLF6 expression was quantified via immunohistochemistry (IHC) and compared to liver samples from 10 non-cirrhotic NAFLD patients with simple steatosis as controls. In another setting, non-cirrhotic liver tissue was obtained from partial liver resection for metastatic surgery in 8 patients. In an established ex-vivo perfusion model, these samples were treated with acetaminophen (APAP) up to 30 hours. KLF6 and HGF (hepatocyte growth factor) mRNA expression was quantified before and after APAP treatment. In a murine model of PHx (n= 6 mice/group), we assessed KLF6 expression before and at different timepoints after PHx. Also, hepatocyte specific KLF6 knockout mice underwent PHx and we performed PCNA staining at different timepoints to assess hepatocyte proliferation, compared to controls (n= 6 mice/group). Results: IHC in ALF patients revealed significant upregulation of KLF6 protein within hepatocytes compared to controls. APAP perfusion of non-cirrhotic liver tissue significantly induced the expression of KLF6 (4.7-fold, p = 0.003) as well as the regeneration-associated molecule HGF (3.9-fold, p = 0.02). In mice, PHx also led to significant induction of KLF6 expression at different timepoints (3.8-fold, p = 0.03). In hepatocyte specific KLF6 knockouts, hepatocyte proliferation, as assessed with PCNA staining was significantly induced at early timepoints (p < 0.05). Conclusion: Here, we were the first to study KLF6 expression in ALF. Our findings suggest an important role for KLF6 in liver regeneration, as KLF6 expression is upregulated in different models of acute liver injury and ALF patients. Hepatocyte proliferation following PHx was induced in mice with KLF6 knockdown, compared to wildtype controls, suggesting a role for KLF6 in hepatic regeneration. Further studies and data analysis will be needed to identify the individual mechanisms for KLF6 mediated effects in acute liver injury.
Published Version
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