The nonalcoholic fatty liver (NAFLD) is one of the most prevalent liver dysfunctions in developed countries. Obesity, diabetes, hyperlipidemia, hyperuricemia and hypertension are several diseases often accompanied with its occurrence. Although the pathogenesis of NAFLD is unclear, linkages to lipid accumulation and metabolism dysfunction have been referred to frequently. 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. Using mass spectrometry, we have established that AMPK phosphorylates KLF10 at Thr189, which subsequently affects the steady state level of KLF10 in cells. We also have come across a sterol regulatory element binding protein 1 (SREBP-1) that is one of the KLF10 target genes through promoter binding. Several studies have demonstrated that facilitated de novo lipogenesis plays an important role in NAFLD and that AMPK and SREBP-1 are key regulators of hepatic lipid metabolism. Knowing that AMPK interacts with KLF10, it is conceivable that different contexts of phosphorylation may lead to disparate consequences such as in SREBP-1. Consistently, our preliminary results suggested that KLF10 is a novel cross-linker between AMPK and SREBP-1 involving NAFLD and steatohepatitis. Thus, an overall examination on the effects of AMPK/KLF10 association and AMPK-Klf10-SREBP-1 signaling cascade on lipid composes, metabolic related genes and mitochondrial function are a must. Information collected will facilitate the clinical development of preventive, diagnostic and therapeutic strategies. The KLF10 knockout mice will be adopted to reconfirm above results. Moreover, clinical fatty liver samples will be collected to identify the epidemiological connection between KLF10 expression and NAFLD in this project.
|Effective start/end date||8/1/16 → 7/31/17|