Abstract
Obesity is the primary risk factor for the pathogenesis of non-alcoholic fatty liver disease (NAFLD), the worldwide prevalence of which continues to increase dramatically. The liver plays a pivotal role in the maintenance of whole-body lipid and glucose homeostasis. This is mainly mediated by the transcriptional activation of hepatic pathways that promote glucose and lipid production or utilization in response to the nutritional state of the body. However, in the setting of chronic excessive nutrition, the dysregulation of hepatic transcriptional machinery promotes lipid accumulation, inflammation, metabolic stress, and fibrosis, which culminate in NAFLD. In this review, we provide our current understanding of the transcription factors that have been linked to the pathogenesis and progression of NAFLD. Using publicly available transcriptomic data, we outline the altered activity of transcription factors among humans with NAFLD. By expanding this analysis to common experimental mouse models of NAFLD, we outline the relevance of mouse models to the human pathophysiology at the transcriptional level.
Highlights
Obesity often results in the dysregulation of lipid and glucose metabolism and is the primary risk factor for the pathogenesis of metabolic disorders, including cardiovascular disease, type 2 diabetes mellitus (T2DM), and non-alcoholic fatty liver disease (NAFLD) [1]
The liver does play a central role in systemic lipid homeostasis and regulates the glucose balance in circulation. This is mediated by the activation of carbohydrate-responsive element-binding protein (ChREBP) in response to increases in plasma glucose and the nuclear localization of PPARγ coactivator 1 alpha (PGC1α), cAMP response element binding protein (Creb), Cyclic AMP-responsive element-binding protein H (CREBH), forkhead protein O1 (FOXO1), and hepatocyte nuclear factor 4α (HNF4α) in response to fasting to promote hepatic glucose production [96] (Table 1)
It is worth mentioning that the activation of ChREBP and C/EBPα were only confirmed in the mouse models using methionine- and choline-deficient diet (MCD) and Western diet (WD) coupled with CCl4, respectively, but they were not detected in human fibrosis datasets
Summary
Obesity often results in the dysregulation of lipid and glucose metabolism and is the primary risk factor for the pathogenesis of metabolic disorders, including cardiovascular disease, type 2 diabetes mellitus (T2DM), and non-alcoholic fatty liver disease (NAFLD) [1]. Obesity-induced maladaptive activation or the inhibition of these transcriptional regulators often exacerbates lipid accumulation, insulin resistance, inflammation, and fibrosis [9]. Lifestyle-Induced Obesity Syndrome model diets to achieve both metabolic and hepatic NASH features within 4 months. Fructose-supplemented drinking water for eight weeks results in simple steatosis in rodents without features of NASH and induces a significant increase in body weight and plasma triglyceride and glucose levels [16]. STAM—STZ-induced T2DM is a well-known experimental model of T2DM and is achieved by the administration of a low dose of STZ shortly after birth, which results in the apoptotic death of insulin-secreting pancreatic islets When this approach is combined with HFD, it can be used as a model for NAFLD and NASH [17]. Key diagnostic parameters of NASH, including ballooning, inflammatory infiltrates and pericellular and bridging fibrosis, are evident following 4 months of HFD and are indistinguishable from human NASH, making this a relevant study model [12]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
