A Regulatory Role of Apoptosis Antagonizing Transcription Factor in the Pathogenesis of Nonalcoholic Fatty Liver Disease and Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is increasing as a cause of liver‐related mortality largely because of the growing burden of nonalcoholic steatohepatitis (NASH). The mechanisms of HCC development in nonalcoholic fatty liver disease (NAFLD) are incompletely understood. We initially identified apoptosis antagonizing transcription factor (AATF) to be associated with HCC in a mouse model of NASH that develops HCC without the addition of specific carcinogens. AATF, also called che‐1, is a transcriptional factor that is highly conserved among eukaryotes. AATF is known to be a central mediator of the cellular responses as it promotes cell proliferation and survival by inducing cell cycle arrest, autophagy, DNA repair, and inhibition of apoptosis. However, the role of AATF in NASH and HCC remains unknown. Here, we provide evidence for AATF as a contributory factor for HCC in NAFLD. AATF overexpression was further verified in human NASH and HCC and multiple human HCC cell lines. Tumor necrosis factor‐α (TNFα), known to be increased in NASH, induced AATF expression. Promoter analysis of AATF revealed a sterol regulatory element binding transcription factor 1‐c (SREBP‐1c) binding site; inhibition of SREBP‐1 by using specific inhibitors as well as small interfering RNA decreased TNFα‐induced AATF expression. AATF interacted with signal transducer and activator of transcription 3 to increase monocyte chemoattractant protein‐1 expression. AATF knockdown decreased cell proliferation, migration, invasion, colony formation, and anchorage‐dependent growth in HCC cell lines. Xenograft of QGY‐7703 HCC cells with AATF stably knocked down into nonobese diabetic scid gamma mice demonstrated reduced tumorigenesis and metastases. Conclusion: AATF drives NAFLD and hepatocarcinogenesis, offering a potential target for therapeutic intervention.

The PPAR α/γ Agonist Saroglitazar Improves Insulin Resistance and Steatohepatitis in a Diet Induced Animal Model of Nonalcoholic Fatty Liver Disease

“…Liver histology analysis, quantitative real-time PCR, Western blots and ELISA. These were performed as previously described 26,28 . A detailed description is provided in supplementary methods.…”

“…We here report the effects of saroglitazar on the development of NASH in the diet-induced animal model of NAFLD (DIAMOND) that recapitulates many of the key elements of human disease especially the histological progression and molecular signature of NASH [26][27][28] . The goals were to demonstrate: (1) efficacy against NASH, (2) impact on the systemic obese, inflammatory state, (3) effects on key pathogenic signaling pathways, metabolome and transcriptome involved in disease pathogenesis.…”

Astaxanthin attenuates hepatic damage and mitochondrial dysfunction in non‐alcoholic fatty liver disease by up‐regulating the FGF21/PGC‐1α pathway

“…The pathogenesis of NAFLD is considered to be a complex multifactorial process. Inflammation, cell apoptosis, and fibrogenesis are all typical damage‐associated changes seen in the NAFLD model and are caused by the lipotoxicity (Garcia‐Monzón et al, 2000; Kumar et al, 2019). We next assessed changes in the liver from both in vivo and in vitro models.…”

A Nomogram Based on a Three-Gene Signature Derived from AATF Coexpressed Genes Predicts Overall Survival of Hepatocellular Carcinoma Patients

“…It is a major mediator of cellular responses that promotes cell proliferation by inducing cell cycle arrest, autophagy, DNA repair, and apoptosis inhibition. AATF is proved to be an important factor contributing to HCC in the formation and progression in previous studies [4]. AATF interacts with signal transducer and activator of transcription 3 to increase the expression of monocyte chemoattractant protein-1, thereby participating in processes including cell proliferation, migration, invasion colony formation, and anchorage-dependent growth.…”