Upregulation of BCL-2 by acridone derivative through gene promoter i-motif for alleviating liver damage of NAFLD/NASH

Abstract

Nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) are global epidemic public health problems with pathogenesis incompletely understood. Hepatocyte excessive apoptosis is a significant symbol for NAFLD/NASH patients, and therefore anti-apoptosis therapy could be used for NAFLD/NASH treatment. Up-regulation of BCL-2 has been found to be closely related with anti-apoptosis. BCL-2 gene promoter region has a C-rich sequence, which can form i-motif structure and play important role in regulating gene transcription. In this study, after extensive screening and evaluation, we found that acridone derivative A22 could up-regulate BCL-2 transcription and translation in vitro and in cells through selective binding to and stabilizing BCL-2 gene promoter i-motif. Our further experiments showed that A22 could reduce hepatocyte apoptosis in NAFLD/NASH model possibly through up-regulating BCL-2 expression. A22 could reduce inflammation, endoplasmic reticulum stress and cirrhosis in high-fat diet-fed mice liver model. Our findings provide a potentially new approach of anti-apoptosis for NAFLD/NASH treatment, and A22 could be further developed as a lead compound for NAFLD/NASH therapy. Our present study first demonstrated that gene promoter i-motif could be targeted for gene up-regulation for extended treatment of other important diseases besides cancer.

Biomimetic nanotherapy: core–shell structured nanocomplexes based on the neutrophil membrane for targeted therapy of lymphoma

“…Apoptosis can be regulated by mitochondrial-mediated endogenous pathway [ 78 ]. Bcl-2 and Bax both belong to the Bcl-2 family; Bcl-2 belongs to anti-apoptotic gene, and Bax belongs to pro-apoptotic gene [ 79 ]. Both of them play an essential role in regulating the process of apoptosis through mitochondrial pathway [ 69 ].…”

The i-Motif as a Molecular Target: More Than a Complementary DNA Secondary Structure

“…Previous studies establishing the i-motif within the BCL2 promoter as a transcriptional activator [46,47] support the premise that stabilization of the BCL2 i-motif in NAFLD and NASH is an effective approach to increase BCL2 levels and prevent hepatocyte apoptosis. Ding Li's laboratory identified an acridone derivative, A22, as a high-affinity stabilizer of the BCL2 i-motif ( Figure 3) [143]. In order to demonstrate preferential selectivity, they tested the compound against the BCL2 G4, duplex DNA, and several other i-motif sequences.…”

“…Moreover, treatment of hepatocytes, grown in palmitic acid oil to mimic the lipid-induced apoptotic environment of NASH, with A22 resulted in a robust increase in cell viability and a decrease in activation of the apoptotic cell death pathway. Since NAFLD and NASH are tightly linked to metabolic syndrome, the authors also examined the effect of A22 treatment on glucose uptake and demonstrated that A22 was significantly more efficacious in stimulating the influx of glucose into hepatocytes compared to the metformin, the frequently prescribed treatment for insulin resistance [143]. Compound A22 also performed well in a NAFLD/NASH mouse model where treatment led to elevated BCL2 levels, less apoptosis, and decreased markers of hepatocyte injury and metabolic syndrome (e.g., weight gain not associated with food intake, insulin resistance, and elevated serum cholesterol and triglycerides).…”

“…Caution is warranted, of course, for approaches that aim to upregulate proto-oncogenes. Treatment with A22 also elicited a dose-dependent increase in BCL2 mRNA and protein in a hepatocellular carcinoma cell line [143], emphasizing the need for further work to fine tune dosage and define the appropriate patient subsets with a favorable risk-benefit ratio to avoid development of therapy-induced malignancies.…”

Oxidative stress in obesity-associated hepatocellular carcinoma: sources, signaling and therapeutic challenges

“…BCL-2 proteins can contribute to hepatic ROS formation, in addition ROS levels can trigger cell death through BCL-2 protein modulation. The antiapoptotic BCL-2 protein is diminished in NAFLD/NASH and its overexpression can reduce hepatic apoptosis [72]. BCL-2 proteins regulate ROS/oxidative stress-mediated apoptosis, but can conversely be regulated by ROS signaling via phosphorylation and ubiquitination [73].…”