Modest Decreases in Endogenous All-<i>trans</i>-Retinoic Acid Produced by a Mouse<i>Rdh10</i>Heterozygote Provoke Major Abnormalities in Adipogenesis and Lipid Metabolism

Yang, Daizhi; Vučković, Marta; Smullin, Carolyn; Kim, Myeongcheol; Lo, Christabel Pui-See; Devericks, Emily; Yoo, Hong Sik; Tintcheva, Milena; Deng, Yinghua; Napoli, Joseph L.

doi:10.2337/db17-0946

Cited by 38 publications

(62 citation statements)

References 50 publications

(50 reference statements)

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“…Recent studies reported by Yang et al (2018) are consistent with this early literature (Bost et al, 2002) regarding the effects of retinoic acid on mouse ES cell commitment to the adipocyte lineage. Yang et al (2018) report that modest decreases in endogenous all-transretinoic acid concentrations in male and female mice heterozygous for the Rdh10 gene were associated with metabolic abnormalities including effects on glucose and insulin sensitivity and adipogenesis. In vitro investigations involving the use of mouse embryonic fibroblasts (MEFs) identified all-trans-retinoic acid levels to be diminished by approximately 50% in cells heterozygous for the Rdh10-null allele.…”

Section: B Vitamin a Vitamin A-related Proteins And Adipose Biologysupporting

confidence: 85%

“…Loss of Aldh1a1 expression was not found to affect retinoic acid synthesis when the MEFs were treated with retinol. Yang et al (2018) conclude that actions of ALDH1A1 not related to its role in vitamin A metabolism likely account for the effects of this enzyme is causing resistance to weight gain. The authors further noted that ALDH1A1 catalyzes other important oxidizations within cells including those of 4-hydroxy-2-nonenal and acrolein, two toxic aldehyde products formed through lipid peroxidation (Makia et al, 2011).…”

Section: Aldh1a1 Actions In Adipocytes and Obesity-aldh1a1 (Raldh1)mentioning

confidence: 87%

“…There is now a general consensus that RDH10 is the major enzyme involved in the synthesis of retinoic acid within the body (Kedishvili, 2013). RDH1 and Dhrs9 too are proposed by some investigators to have a physiologic role in this metabolic process (Kedishvili, 2013;Yang et al, 2017;Yang et al, 2018). The RDHs, ones that are now understood to be important for catalyzing retinol oxidation as the first enzymatic step needed for retinoic acid formation, are members of the short chain dehydrogenase/reductase protein family.…”

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confidence: 99%

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Vitamin A signaling and homeostasis in obesity, diabetes, and metabolic disorders

Blaner

2019

Pharmacology & Therapeutics

200

174

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Much evidence has accumulated in the literature over the last fifteen years that indicates vitamin A has a role in metabolic disease prevention and causation. This literature proposes that vitamin A can affect obesity development and the development of obesity-related diseases including insulin resistance, type 2 diabetes, hepatic steatosis and steatohepatitis, and cardiovascular disease. Retinoic acid, the transcriptionally active form of vitamin A, accounts for many of the reported associations. However, a number of proteins involved in vitamin A metabolism, including retinolbinding protein 4 (RBP4) and aldehyde dehydrogenase 1A1 (ALDH1A1, alternatively known as retinaldehyde dehydrogenase 1 or RALDH1), have also been identified as being associated with metabolic disease. Some of the reported effects of these vitamin A-related proteins are proposed to be independent of their roles in assuring normal retinoic acid homeostasis. This review will consider both human observational data as well as published data from molecular studies undertaken in rodent models and in cells in culture. The primary focus of the review will be on the effects that vitamin A per se and proteins involved in vitamin A metabolism have on adipocytes, adipose tissue biology, and adipose-related disease, as well as on early stage liver disease, including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

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Section: B Vitamin a Vitamin A-related Proteins And Adipose Biologysupporting

confidence: 85%

Section: Aldh1a1 Actions In Adipocytes and Obesity-aldh1a1 (Raldh1)mentioning

confidence: 87%

mentioning

confidence: 99%

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Vitamin A signaling and homeostasis in obesity, diabetes, and metabolic disorders

Blaner

2019

Pharmacology & Therapeutics

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174

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“…In addition, a recent study in mice heterozygous for Rdh10 knockout found increased steatosis on a high-fat diet despite only a modest decrease in hepatic RA. (45) This suggests unique substrate specificity and is consistent with retinoids being the substrate for HSD17B13. Ongoing in vivo experiments are aimed at confirming these findings.…”

Section: Discussionsupporting

confidence: 70%

17‐Beta Hydroxysteroid Dehydrogenase 13 Is a Hepatic Retinol Dehydrogenase Associated With Histological Features of Nonalcoholic Fatty Liver Disease

et al. 2019

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Nonalcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease. A single‐nucleotide polymorphism (SNP), rs6834314, was associated with serum liver enzymes in the general population, presumably reflecting liver fat or injury. We studied rs6834314 and its nearest gene, 17‐beta hydroxysteroid dehydrogenase 13 (HSD17B13), to identify associations with histological features of NAFLD and to characterize the functional role of HSD17B13 in NAFLD pathogenesis. The minor allele of rs6834314 was significantly associated with increased steatosis but decreased inflammation, ballooning, Mallory‐Denk bodies, and liver enzyme levels in 768 adult Caucasians with biopsy‐proven NAFLD and with cirrhosis in the general population. We found two plausible causative variants in the HSD17B13 gene. rs72613567, a splice‐site SNP in high linkage with rs6834314 (r2 = 0.94) generates splice variants and shows a similar pattern of association with NAFLD histology. Its minor allele generates simultaneous expression of exon 6‐skipping and G‐nucleotide insertion variants. Another SNP, rs62305723 (encoding a P260S mutation), is significantly associated with decreased ballooning and inflammation. Hepatic expression of HSD17B13 is 5.9‐fold higher (P = 0.003) in patients with NAFLD. HSD17B13 is targeted to lipid droplets, requiring the conserved amino acid 22‐28 sequence and amino acid 71‐106 region. The protein has retinol dehydrogenase (RDH) activity, with enzymatic activity dependent on lipid droplet targeting and cofactor binding site. The exon 6 deletion, G insertion, and naturally occurring P260S mutation all confer loss of enzymatic activity. Conclusion: We demonstrate the association of variants in HSD17B13 with specific features of NAFLD histology and identify the enzyme as a lipid droplet–associated RDH; our data suggest that HSD17B13 plays a role in NAFLD through its enzymatic activity.

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“…We are aware that retinoid plasma concentrations per se may not necessarily have a dramatic biological impact. However it has been demonstrated that very subtle changes in the tissue retinoid content can have substantial functional effects, particularly on the transcriptional level [ 32 ]. It is also possible that longer cold challenges may have even more pronounced effects on retinoid metabolism and biological outcomes, such as WAT browning.…”

Section: Discussionmentioning

confidence: 99%

Intact vitamin A transport is critical for cold-mediated adipose tissue browning and thermogenesis

Fenzl

Kulterer²,

Spirk³

et al. 2020

Molecular Metabolism

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Objective Transformation of white into brown fat (“browning”) reduces obesity in many preclinical models and holds great promise as a therapeutic concept in metabolic disease. Vitamin A metabolites (retinoids) have been linked to thermogenic programming of adipose tissue; however, the physiologic importance of systemic retinoid transport for adipose tissue browning and adaptive thermogenesis is unknown. Methods We performed cold exposure studies in mice and humans and used a genetic model of defective vitamin A transport, the retinol binding protein deficient (Rbp −/- ) mouse, to study the effects of cooling on systemic vitamin A and the relevance of intact retinoid transport on cold-induced adipose tissue browning. Results We show that cold stimulation in mice and humans leads to an increase in circulating retinol and its plasma transporter, Rbp. In Rbp −/- mice, thermogenic programming of adipocytes and oxidative mitochondrial function are dramatically impaired in subcutaneous white fat, which renders Rbp −/- mice more cold-sensitive. In contrast, retinol stimulation in primary human adipocytes promotes thermogenic gene expression and mitochondrial respiration. In humans, cold-mediated retinol increase is associated with a shift in oxidative substrate metabolism suggestive of higher lipid utilisation. Conclusions Systemic vitamin A levels are regulated by cold exposure in mice and humans, and intact retinoid transport is essential for cold-induced adipose tissue browning and adaptive thermogenesis.

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Modest Decreases in Endogenous All-trans-Retinoic Acid Produced by a MouseRdh10Heterozygote Provoke Major Abnormalities in Adipogenesis and Lipid Metabolism

Cited by 38 publications

References 50 publications

Vitamin A signaling and homeostasis in obesity, diabetes, and metabolic disorders

Vitamin A signaling and homeostasis in obesity, diabetes, and metabolic disorders

17‐Beta Hydroxysteroid Dehydrogenase 13 Is a Hepatic Retinol Dehydrogenase Associated With Histological Features of Nonalcoholic Fatty Liver Disease

Intact vitamin A transport is critical for cold-mediated adipose tissue browning and thermogenesis

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