Selective inhibition of CBP/p300 HAT by A-485 results in suppression of lipogenesis and hepatic gluconeogenesis

Abstract

The histone acetyltransferases CREB-binding protein (CBP) and its paralogue p300 are transcriptional coactivators which are essential for a multitude of signaling pathways and energy homeostasis. However, the role of CBP/p300 HAT domain in regulating energy balance is still unclear. Here, C57BL/6 mice fed with either normal chow diet (NCD) or high-fat diet (HFD) were administrated with A-485, a recently reported selective inhibitor of CBP/p300 HAT activity for 1 week and the metabolic change was analyzed. The white adipose tissue (WAT) weight and adipocyte size were reduced in A-485-administrated mice, with decreased expressions of lipogenic genes and transcriptional factors. In the liver of A-485-treated mice, the lipid content and lipogenic gene expressions were lowered while the binding of forkhead box O1 (FOXO1) to glucose-6-phosphatase (G6Pc) promoter was reduced, leading to decreased expression of G6Pc. In primary mouse hepatocytes, A-485 abolished cAMP-elicited mRNA expressions of key gluconeogenic enzymes and promoted FOXO1 protein degradation via increasing its ubiquitination. Thus, A-485 inhibits lipogenesis in WAT and liver as well as decreases hepatic glucose production via preventing FOXO1 acetylation, leading to its protein degradation through a proteasome-dependent pathway. The specific inhibition of CBP/p300 HAT will provide a novel therapeutic approach for metabolic diseases.

Alterations of Gut Microbiota by Overnutrition Impact Gluconeogenic Gene Expression and Insulin Signaling

“…Moreover, in HFD-fed mice, depletion of liver P300 by shRNA significantly decreased liver glucose production, and the inhibition of P300 acetyltransferase by C646 or A-485 [ 62 , 63 , 64 , 65 ] significantly reduced glucose production in primary hepatocytes and the mRNA levels of G6pc [ 59 , 66 ]. Since the acetylation of CRTC2 by nuclear P300 reduces CRTC2 degradation [ 46 ], elevated P300 protein levels could augment gluconeogenic gene expression by increasing CRTC2 protein levels in HFD-fed mice ( Figure 1 B).…”

“…Curcumin, an inhibitor for both P300 and CBP acetyltransferase activity, has been used to alleviate hyperglycemia in diabetic patients and animal models [ 121 , 122 , 123 ]. A-485, a more potent and specific inhibitor of both P300 and CBP acetyltransferase activity, alleviated fasting blood glucose levels in HFD-fed mice [ 66 ]. C646, a P300 acetyltransferase-specific inhibitor, significantly improved hyperglycemia and improved insulin sensitivity in obese mice [ 59 ].…”

Epigenetics of Hepatic Insulin Resistance

“…In functional studies, p300 overexpression in mice was reported to cause hepatic steatosis, insulin resistance, and inflammation (27). Inhibiting CBP/p300 in mouse liver decreased hepatic lipid content and the expression of lipogenic genes in vivo and also reduced the expression of gluconeogenic genes in primary mouse hepatocytes (130). While this study reported no difference in in vivo insulin sensitivity, mice had reduced fasting glucose and lower glucose levels after glucose loading (130).…”

“…Inhibiting CBP/p300 in mouse liver decreased hepatic lipid content and the expression of lipogenic genes in vivo and also reduced the expression of gluconeogenic genes in primary mouse hepatocytes (130). While this study reported no difference in in vivo insulin sensitivity, mice had reduced fasting glucose and lower glucose levels after glucose loading (130). Similarly, CREB activity is positively associated with hepatic IR and NAFLD in mice (131) and its knockdown in mouse liver decreased hepatic and circulating lipid levels and improved insulin sensitivity (132).…”

Synthesis and Biological Evaluation of Spirocyclic Chromane Derivatives as a Potential Treatment of Prostate Cancer

“…It competed with acetyl-CoA for the active site of p300, and selectively inhibited the proliferation of haematological and solid cancer cell lines, such as castration-resistant androgen receptor-positive prostate cancer [22,23]. In addition, A-485 also showed a certain positive effect on liver damage and metabolic diseases [24,25]. On the basis of A-485, Zhou et al identified a preclinical candidate B026 (5) with excellent pharmacological properties with the assistance of artificial intelligence and further optimization [26].…”