Retinoic Acid Receptor β Stimulates Hepatic Induction of Fibroblast Growth Factor 21 to Promote Fatty Acid Oxidation and Control Whole-body Energy Homeostasis in Mice

Abstract

Background: All-trans-retinoic acid ameliorates glucose intolerance and insulin resistance in diabetes. Results: The gene transcription of hepatic Fgf21 and its metabolic effects on lipid oxidation, ketogenesis, and whole-body energy expenditure are up-regulated by RAR␤ activation. Conclusion: Hepatic RAR␤ stimulates FGF21 production via the RARE. Significance: The hepatic RAR-FGF21 axis is a potential druggable target for treating metabolic syndrome.

All-Trans-Retinoic Acid Enhances Mitochondrial Function in Models of Human Liver

“…atRA has been shown to suppress PPARg2 expression and decrease hepatic lipid accumulation in diet-induced obese mice by activating RARa (Kim et al, 2014). After adenoviral overexpression of RARb, atRA treatment increased the expression of fatty acid oxidative genes CPT1a and MCAD in mouse liver and in HepG2 cells (Li et al, 2013). atRA also enhanced fatty acid oxidation and ketogenesis via RAR activation and FGF21 induction in HepG2 cells (Amengual et al, 2012;Li et al, 2013).…”

“…After adenoviral overexpression of RARb, atRA treatment increased the expression of fatty acid oxidative genes CPT1a and MCAD in mouse liver and in HepG2 cells (Li et al, 2013). atRA also enhanced fatty acid oxidation and ketogenesis via RAR activation and FGF21 induction in HepG2 cells (Amengual et al, 2012;Li et al, 2013). Although the data presented in this study in human hepatocytes, HepG2 cells, and in mice are in agreement with a role of atRA at endogenous concentrations in increasing fatty acid b-oxidation, ATP production, mitochondrial function, and mitochondrial biogenesis, the data do not support a role of RARs in how atRA regulates these processes.…”

“…Hepatocyte-specific RAR knockout mice develop microvesicular steatosis, hepatocellular carcinoma, decreased mitochondrial fatty acid oxidation, and increased peroxisomal and microsomal fatty acid oxidation presumably due to deficient atRA signaling (Yanagitani et al, 2004). Similarly, in normal mice atRA enhances fatty acid oxidation and ketogenesis via RAR activation and FGF21 induction (Amengual et al, 2012;Li et al, 2013). In agreement with a role of atRA in maintaining lipid homeostasis in the liver, decrease of hepatic atRA concentrations via inhibition of atRA synthesis in mice led to microvesicular vacuolation but without a change in liver triglycerides (Paik et al, 2014).…”

Longer Duration and Earlier Age of Onset of Paternal Betel Chewing and Smoking Increase Metabolic Syndrome Risk in Human Offspring, Independently, in a Community-Based Screening Program in Taiwan

“…23 Although the evidence we present is compatible with epigenetic effects of chewing A catechu (and of smoking), they could be related to underlying genetic variants, such as the DRD2 Taq1A, DRD4 48 bp VNTR and OPRM1 genotypes reported to play a role in the development of nicotine craving in young novice smokers, 37 or those found to be associated with dopamine binding potential, such as the OPRM1 A118G genotype. 38 There also is evidence supporting a link between genetic variants and MetS-related disorders.…”

“…, 21 BEX1 and LDOC1, 22 and the retinoic acid receptor β, 23 and since specific arecoline-induced epigenetic changes have been reported. 24 We have, therefore, hypothesized that the younger the father begins exposure to areca nut chewing, or smoking, and the longer he has chewed or smoked before offspring conception, the more likely is the early development of MetS in his offspring because of the cumulative effects of exposure to causative agents provided by these habits, which would further support the possibility of causal genetic or epigenetic changes.…”