Characterization of the role of KLF6 in regeneration of steatotic livers.

• Applicant: Professor Dr. Lars Peter Bechmann (†)
• Subject Area: Gastroenterology
• Term: from 2013 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 242483332

Non-alcoholic fatty liver disease (NAFLD) is currently the most prevalent liver disease in Western societies with a prevalence of up to 35%. Non-alcoholic steatohepatitis (NASH), the chronic-progressive manifestation of NAFLD is associated with liver cirrhosis and hepatocellular cancer (HCC). Obesity, inducing peripheral lipolysis, cytokine expression and insulin resistance are widely accepted as underlying mechanisms, promoting hepatic steatosis and inflammation. Obesity and NAFLD are independent risk factors for acute liver failure (ALF) and associated with a lethal outcome. Empirical data, prospective and animal studies have shown a disadvantage of steatotic livers as donor organs with reduced regenerative capacity. Thus, transplantation of steatotic livers is widely restricted, which is of particular interest in the current situation of organ donor shortage. Interestingly, some recent studies, showing a potential hepatoprotective effect of hepatic triglyceride accumulation, initiated a discussion about this paradigm. The underlying mechanisms, which link hepatic steatosis to liver regeneration, are only scarcely understood. The applicant has shown a relevant role for the extent and the pattern of hepatic cell death (apoptosis vs. necrosis) in the clinical course of ALF and identified a mechanistic link between fatty acid transport molecules and apoptosis rate as an indicator of hepatocyte damage in NAFLD. As a postdoctoral fellow in the lab of Scott Friedman at Mount Sinai School of Medicine, Dr. Bechmann found a novel role for the tumor suppressor gene Krüppel-Like-Factor 6 (KLF6) as a transcriptional activator of liver glucokinase, a key molecule in hepatic insulin sensitivity. Furthermore, he identified KLF6 as a posttranscriptional activator of peroxisome proliferator-activated receptor alpha (PPARa) via repression of micro-RNA 10b. PPARa and other nuclear receptors are important modulators of hepatic glucose- and lipid metabolism as well as liver regeneration. As an important tumor suppressor gene, KLF6 is known to affect both, apoptosis and cell proliferation associated signaling pathways. Yet, no data are available on a potential role of KLF6 in liver regeneration, especially in the context of hepatic steatosis. Preliminary data suggest improved liver regeneration in KLF6 deficient mice. Thus, the aims of this study are to i) characterize the role of KLF6 in liver regeneration in vivo, cell culture and in samples from ALF patients, ii) the role of KLF6 on hepatocellular metabolic pathways and nuclear receptor signaling, and iii) discriminate the metabolic effects from direct pro-apoptotic and anti-proliferative effects of the growth suppressor KLF6 on liver regeneration.

• DFG Programme: Research Grants