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

Abstract

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Retinoids in the Pathogenesis and Treatment of Liver Diseases

“…Another primary source of fatty acids in the liver is from the influx of free fatty acids from blood [ 69 ], including oleate and palmitate [ 96 ]. There have been few studies of the impact of natural retinoids on hepatic influx of free fatty acids; however, we found that a RARβ2-selective agonist inhibits high-fat-diet induced increases in the mRNA and protein levels of the fatty acid transporter CD36, indicating that this agonist attenuates free fatty acid influx to the liver [ 90 ] ( Figure 2 ). To date, we found no studies reporting the effects of retinoids on lipid export from the liver.…”

“…We discovered that highly selective synthetic RARβ2 agonists reduce the mRNA and protein levels of multiple gene products (including SREBF, PPARG, and FASN) that are involved in lipogenesis in the liver in a high-fat-diet (HFD)-induced NAFLD mouse model [ 89 , 90 ] ( Figure 2 ). Fructose and sucrose intake promotes de novo lipogenesis in the liver [ 91 , 92 ], and a recent pre-clinical study indicates that a fructokinase (also called ketohexokinase) inhibitor improves NAFLD/NASH [ 91 ].…”

“…Fructose and sucrose intake promotes de novo lipogenesis in the liver [ 91 , 92 ], and a recent pre-clinical study indicates that a fructokinase (also called ketohexokinase) inhibitor improves NAFLD/NASH [ 91 ]. We discovered that, in a high-fat diet mouse NAFLD model, one of the key mechanisms by which a highly selective synthetic RARβ2 agonist suppresses lipid accumulation in the liver could be inhibition of fructose metabolism [ 90 ] ( Figure 2 ).…”

“…In line with this, RARβ2 selective agonists increase the transcript levels of genes that promote and mediate mitochondrial fatty acid β-oxidation, including PPARα and CPT1A [ 89 ]. In contrast to the effects of RARβ2 selective agonists on liver steatosis in HFD-induced NAFLD models [ 89 , 90 , 94 ], the RARα agonist Am 80 exacerbates [ 95 ] and the RARγ agonist CD1530 [ 94 ] has no major effect on liver steatosis in these models, respectively. Although murine genetic studies demonstrate a role for RARα and RARβ in the regulation of fatty acid oxidation in the liver [ 56 , 93 ], studies using RAR-specific agonists can also further enhance understanding of the effects of specific RAR activation in mediating hepatic fatty acid oxidation.…”

Tormentic Acid Ameliorates Hepatic Fibrosis in vivo by Inhibiting Glycerophospholipids Metabolism and PI3K/Akt/mTOR and NF-κB Pathways: Based on Transcriptomics and Metabolomics

“…Metabolomics analysis can provide the global metabolic profile and identify the differently expressed metabolites. The integrative analysis of transcriptome and metabolome has been increasingly used to investigate the complicated mechanisms of liver diseases ( Zhao et al, 2020 ; Tang et al, 2021 ).…”