Study a Novel Klf10 (Kruppel-Like Transcription Factor10) Regulated Mechanism in Non-Alcoholic Fatty Liver Disease (NAFLD)

Nonalcoholic fatty liver disease (NAFLD) is one of the most frequent causes of liver dysfunction. Its prevalence has been and is continuously on the rise markedly. Spectrum of disease extends to nonalcoholic steatohepatitis that can lead to cirrhosis and hepatocellular carcinoma. NAFLD has a strong association with type 2 diabetes mellitus (T2M). In particular, through interrelated metabolic pathways currently only partly understood, diabetes appears to accelerate the progression of NAFLD to nonalcoholic steatohepatitis with varying degrees of liver fibrosis. Although the pathogenesis of NAFLD is unclear, NAFLD has been linked to lipid accumulation and metabolism dysfunction. Klf10 is a tumor suppressor; its expression is inversely correlated with clinical hepatic carcinoma and pancreatic cancer stages. Klf10 protein expression also is tightly associated with circadian clock, lipid and carbohydrate metabolism events. In our studies, Klf10-deficient mice present T2M syndrome such as hyperinsulinemia. However, the regulatory mechanism and its biological meaning in NAFLD and T2M have not been identified. In our laboratory, we have initially identified several kinases that modulated Klf10 through phosphorylation on specific sites. One of them is AMP-activated kinase (AMPK), which is considered as a cellular energy sensor. While using ChIP-chip to elucidate the novel target genes and signaling cascades of Klf10, we also have come across a sterol regulatory element binding protein 1 (SREBP-1) as one of the target genes that may be regulated by Klf10 through promoter binding. Several studies have demonstrated that facilitated de novo lipogenesis plays an important role in NAFLD and that AMPK and SREBP1 are key regulators of hepatic lipid metabolism. Recent studies revealed that, in NAFLD, insulin signaling via Insulin receptor substrate 1 causes the up-regulation of SREBP-1, leading to the increased synthesis of fatty acids in hepatocytes together with a negative feedback regulation via AMPK. Still, the mechanism of how AMPK regulates SREBP-1 is unknown. Knowing that AMPK interacts with Klf10 (from our preliminary results), it is conceivable that different contexts of phosphorylation may lead to disparate consequences such as SREBP-1. Consistently, our preliminary results suggested that Klf10 is a novel cross-linker between AMPK and SREBP-1 involving lipid homeostasis. Thus, an overall examine on the effects of AMPK/Klf10 association and AMPK-Klf10-SREBP1 signaling cascade on lipid metabolism in physiological and pathological conditions is a must. Information collected will facilitate the clinical development of preventive, diagnostic and therapeutic strategies.