The roles of Src homology 3 domain binding kinase 1 in lipid metabolism

Abstract

Mitochondrial fatty acid β-oxidation (FAO) in the liver plays a fundamental role in systemic energy homeostasis and redox balance. FAO in the liver is reprogrammed to meet metabolic needs in response to nutrient challenges. Dysregulated FAO activity is associated with metabolic disorders, such as fatty liver diseases and insulin resistance. Nevertheless, the current pharmacotherapeutic strategies for metabolic syndromes are limited and unsatisfied because of periodical efficacy and side effects. The delineation of novel regulators and mechanisms controlling hepatic FAO will provide new opportunities for the growing number of patients worldwide. This study aims to characterize the functional role and molecular mechanisms of Src Homology 3 Domain Binding Kinase 1 (SBK1), a member of the uncharacterized new kinase family 1 (NKF1), in hepatic lipid metabolism. Enhanced SBK1 expression was found in the livers of mice that underwent high-fat diet feeding, diet restriction, or exhaustive exercise. Differential regulation of SBK1 induced by nutrient depletion, metabolic hormones, and intercellular fatty acids in the primary hepatocytes isolated from mice and goldfish suggested the energy stress induced SBK1 expression was hepatocyte autonomous. RNA sequencing analysis revealed the defective expression of hepatic genes in lipid metabolism in liver specific SBK1 knockout (LSKO) mice from the perspectives of differential gene expression and alternative splicing. Biochemical assays substantially confirmed the impaired hepatic lipid metabolism resulted from reduced PPAR activity in the livers and primary hepatocytes isolated from LSKO mice compared to the SBK1 Fl/Fl control mice during fasting. On the other hand, adenovirus-based overexpression of SBK1 led to enhanced PPAR activity and FAO in the liver. Further in vivo and ex vivo investigations addressed SBK1 acted as a brake on p21 expression to abolish the interaction between p21 and PPAR, thus promoting the PPAR activity-controlled FAO. Mechanistically, SBK1 possibly phosphorylates the tyrosine phosphatase PTPN23 to eliminate the activation of STAT3 Y705, further inhibiting the transcription of p21. Collectively, our data suggests that SBK1 is a novel regulator of metabolic adaptation through the p21-PPAR signaling to activate FAO in the liver.