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

Yu, Li; Wong, Kelly; Walsh, Kenneth; Gao, Bin; Zang, Mengwei

doi:10.1074/jbc.m112.429852

Cited by 88 publications

(78 citation statements)

References 53 publications

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“…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).…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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All-trans-retinoic acid (atRA) is the active metabolite of vitamin A. The liver is the main storage organ of vitamin A, but activation of the retinoic acid receptors (RARs) in mouse liver and in human liver cell lines has also been shown. Although atRA treatment improves mitochondrial function in skeletal muscle in rodents, its role in modulating mitochondrial function in the liver is controversial, and little data are available regarding the human liver. The aim of this study was to determine whether atRA regulates hepatic mitochondrial activity. atRA treatment increased the mRNA and protein expression of multiple components of mitochondrial b-oxidation, tricarboxylic acid (TCA) cycle, and respiratory chain. Additionally, atRA increased mitochondrial biogenesis in human hepatocytes and in HepG2 cells with and without lipid loading based on peroxisome proliferator activated receptor gamma coactivator 1a and 1b and nuclear respiratory factor 1 mRNA and mitochondrial DNA quantification. atRA also increased b-oxidation and ATP production in HepG2 cells and in human hepatocytes. Knockdown studies of RARa, RARb, and PPARd revealed that the enhancement of mitochondrial biogenesis and b-oxidation by atRA requires peroxisome proliferator activated receptor delta. In vivo in mice, atRA treatment increased mitochondrial biogenesis markers after an overnight fast. Inhibition of atRA metabolism by talarozole, a cytochrome P450 (CYP) 26 specific inhibitor, increased the effects of atRA on mitochondrial biogenesis markers in HepG2 cells and in vivo in mice. These studies show that atRA regulates mitochondrial function and lipid metabolism and that increasing atRA concentrations in human liver via CYP26 inhibition may increase mitochondrial biogenesis and fatty acid b-oxidation and provide therapeutic benefit in diseases associated with mitochondrial dysfunction.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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“…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.…”

Section: Discussionmentioning

confidence: 47%

“…, 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.…”

Section: Ink4amentioning

confidence: 99%

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

et al. 2016

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Original research article BACKGROUND: Transgenerational effects of paternal Areca catechu nut chewing on offspring metabolic syndrome (MetS) risk in humans, on obesity and diabetes mellitus experimentally, and of paternal smoking on offspring obesity, are reported, likely attributable to genetic and epigenetic effects previously reported in betel-associated disease. We aimed to determine the effects of paternal smoking, and betel chewing, on the risks of early MetS in human offspring. METHODS:The 13 179 parent-child trios identified from 238 364 Taiwanese aged ≥20 years screened at 2 community-based integrated screening sessions were tested for the effects of paternal smoking, areca nut chewing, and their duration prefatherhood on age of detecting offspring MetS at screen by using a Cox proportional hazards regression model. RESULTS:Offspring MetS risks increased with prefatherhood paternal areca nut usage (adjusted hazard ratio, 1.77; 95% confidence interval [CI], 1.23-2.53) versus nonchewing fathers (adjusted hazard ratio, 3.28; 95% CI, 1.67-6.43) with >10 years paternal betel chewing, 1.62 (95% CI, 0.88-2.96) for 5 to 9 years, and 1.42 (95% CI, 0.80-2.54) for <5 years betel usage prefatherhood (P trend =0.0002), with increased risk (adjusted hazard ratio, 1.95; 95% CI, 1.26-3.04) for paternal areca nut usage from 20 to 29 years of age, versus from >30 years of age (adjusted hazard ratio,1.61; 95% CI, 0.22-11.69). MetS offspring risk for paternal smoking increased dosewise (P trend <0.0001) with earlier age of onset (P trend= 0.0009), independently. CONCLUSIONS:Longer duration of paternal betel quid chewing and smoking, prefatherhood, independently predicted early occurrence of incident MetS in offspring, corroborating previously reported transgenerational effects of these habits, and supporting the need for habit-cessation program provision.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

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CO as a Protective Mediator of Liver Injury

Joe¹,

Park²,

Do³

et al. 2022

Carbon Monoxide in Drug Discovery

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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

Cited by 88 publications

References 53 publications

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

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

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

CO as a Protective Mediator of Liver Injury

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