Abstract
Nonalcoholic fatty liver disease (NAFLD) is a rapidly emerging global health-problem. NAFLD encompasses a range of conditions associated with hepatic steatosis, aberrant accumulation of fat in hepatocytes. Although obesity and metabolic syndrome are considered to have a strong association with NAFLD, genetic factors that predispose liver to NAFLD and molecular mechanisms by which excess hepatic lipid develops remain largely unknown. We report that the transcription cofactor CRTC1 confers broad spectrum protection against hepatic steatosis development. CRTC1 directly interferes with the expression of genes regulated by lipogenic transcription factors, most prominently liver x receptor α (LXRα). Accordingly, Crtc1 deficient mice develop spontaneous hepatic steatosis in young age. As a cyclic AMP effector, CRTC1 mediates anti-steatotic effects of calorie restriction (CR). Notably, CRTC1 also mediates anti-lipogenic effects of bile acid signaling, whereas it is negatively regulated by miR-34a, a pathogenic microRNA upregulated in a broad spectrum of NAFLD. These patterns of gene function and regulation of CRTC1 are distinct from other CR-responsive proteins, highlighting critical protective roles that CRTC1 selectively plays against NAFLD development, which in turn provides novel opportunities for selectively targeting beneficial therapeutic effects of CR.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder worldwide, with its prevalence estimated to be up to 40% in adults worldwide[1,2]
We found that CRTC1 mediates beneficial anti-lipogenic effects of bile acid-mediated signaling in the enterohepatic system[17], whereas its protective activities can be compromised by miR-34a, a pathogenic microRNA upregulated in a broad spectrum of NAFLD18
Ectopic expression of CRTC1 in 293ETN cells[3], in which expression of endogenous CRTC1 is low, strongly inhibited activation of transcriptional reporters driven by the promoter of fatty acid synthase (FASN): both basal activity and FASN activation triggered by coexpressed lipogenic transcription factors, including liver x receptor α (LXRα),active nuclear sterol regulatory element binding protein 1c (SREBP1c), or carbohydrate responsive element binding protein (ChREBP) (Fig. 1a)
Summary
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder worldwide, with its prevalence estimated to be up to 40% in adults worldwide[1,2]. A majority of patients with this isolated hepatic steatosis present benign and non-progressive disease, a subset of patients develops superimposed pathological inflammation and hepatocyte injury, with or without fibrosis, which characterize nonalcoholic steatohepatitis (NASH). There is currently no effective pharmacological treatment of NAFLD exist This can be attributed largely to our still very limited understanding of the underlying pathophysiology of NAFLD. NAFLD has been demonstrated to have a strong association with obesity, insulin resistance and type 2 diabetes, genetic factors that predispose liver to NAFLD and molecular mechanisms by which hepatic steatosis develops and its further progression to more advanced forms of NAFLD remain largely unknown. We identified that CRTC1, a member of the family of CRTC transcription co-factors, exhibited great potential for alleviating various pathological lipid accumulation and inflammation underlying NAFLD development, and selected it for further study. (cAMP) or calcium triggers their dephosphorylation and nuclear translocation, which mediate downstream effector functions by interacting with various transcriptional factors and co-factors over relevant promoters
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