A retinoic acid receptor β2 agonist attenuates transcriptome and metabolome changes underlying nonalcohol-associated fatty liver disease

Xiao-Han Tang,Marta Melis,Changyuan Lu,Andrew Rappa,Tuo Zhang,Jose Jessurun,Steven S Gross,Lorraine J Gudas

doi:10.1016/j.jbc.2021.101331

Abstract

Nonalcohol-associated fatty liver disease (NAFLD) is characterized by excessive hepatic accumulation of fat that can progress to steatohepatitis, and currently, therapeutic options are limited. Using a high-fat diet (HFD) mouse model of NAFLD, we determined the effects of the synthetic retinoid, AC261066, a selective retinoic acid receptor β2 (RARβ2) agonist, on the global liver transcriptomes and metabolomes of mice with dietary-induced obesity (DIO) using genome-wide RNA-seq and untargeted metabolomics. We found that AC261066 limits mRNA increases in several presumptive NAFLD driver genes, including Pklr, Fasn, Thrsp, and Chchd6. Importantly, AC261066 limits the increases in the transcript and protein levels of KHK, a key enzyme for fructose metabolism, and causes multiple changes in liver metabolites involved in fructose metabolism. In addition, in cultured murine hepatocytes, where exposure to fructose and palmitate results in a profound increase in lipid accumulation, AC261066 limits this lipid accumulation. Importantly, we demonstrate that in a human hepatocyte cell line, RARβ is required for the inhibitory effects of AC261066 on palmitate-induced lipid accumulation. Finally, our data indicate that AC261066 inhibits molecular events underpinning fibrosis and exhibits anti-inflammatory effects. In conclusion, changes in the transcriptome and metabolome indicate that AC261066 affects molecular changes underlying multiple aspects of NAFLD, including steatosis and fibrosis. Therefore, we suggest that AC261066 may have potential as an effective therapy for NAFLD.

Highlights

ABSTRACTNonalcohol associated fatty liver diseaseNon-alcohol-associated fatty liver disease (NAFLD), which is defined as the (NAFLD) is characterized by excessive hepatic accumulation of intrahepatic triglycerides accumulation of fat that can progress to without excessive alcohol intake and is usually steatohepatitis, and currently, therapeutic associated with obesity, has become a primary options are limited
225 transcripts increased in the high fat diet (HFD)/chow were reduced in the HFD+AC261066/HFD, while 286 transcripts decreased in the HFD/chow were increased in the HFD+AC261066/HFD (Table S2)
HFD treatment induces the HFD-induced transcript changes in the increases in multiple transcripts involved in liver

Summary

Introduction

ABSTRACTNonalcohol associated fatty liver diseaseNon-alcohol-associated fatty liver disease (NAFLD), which is defined as the (NAFLD) is characterized by excessive hepatic accumulation of intrahepatic triglycerides accumulation of fat that can progress to without excessive alcohol intake and is usually steatohepatitis, and currently, therapeutic associated with obesity, has become a primary options are limited. (DEGs)) differed significantly between the induced liver steatosis in mice, indicating that livers from HFD fed and chow fed mice, activation of retinoic acid signaling could be including increases in 1,942 genes and novel therapy for NAFLD [6].

Results

Conclusion