A9 - Aldehyde oxidase contributes to all-trans-retinoic acid biosynthesis in human liver

Zhong, Guo; Seaman, Chris J.; Xi, Huaqing; Paragas, Erickson M.; Jones, Jeffrey P.; Isoherranen, Nina

doi:10.1016/j.dmpk.2020.04.263

Cited by 2 publications

(8 citation statements)

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“…[ALDH1A1], [ALDH1A2], and [AOX] are the measured expression levels (mean of the replicate analyses of each sample) in units of pmol/mg S9 protein for each enzyme in the individual donor S9 fractions from a given depot based on the LC‐MS/MS quantification. The K m and k cat values are as previously measured for recombinant ALDH1A1 ( K m = 285 nM, k cat = 1.1 min −1 ), 20 ALDH1A2 ( K m = 56 nM, k cat = 3.7 min −1 ), 20 and AOX ( K m = 1500 nM, k cat = 3.6 min −1 ) 21 . The average fold error (afe) of predictions of at RA formation velocity in adipose tissue S9 fractions was calculated using Equation 2.

afe = 10^{\frac{1}{normaln} \sum normallog \frac{v_{predicted}}{v_{observed}}}

…”

Section: Methodsmentioning

confidence: 86%

“…All mass spectrometry grade solvents were purchased from Thermo Fisher Scientific (Waltham, MA). Stable isotope labeled (SIL) peptides labeled with [ 13 C 6 15 N 2 ] arginine and [ 13 C 6 15 N 2 ] lysine were from Thermo Fisher Scientific (Waltham, MA) and used as internal standards (IS) for AOX, aldehyde dehydrogenase 1 family member A1 (ALDH1A1) and family member A2 (ALDH1A2) protein quantification 21,22 . Human recombinant ALDH1A1, ALDH1A2, and AOX were expressed and purified as described previously and used as quantification standards 21 …”

Section: Methodsmentioning

confidence: 99%

“…[18][19][20] In addition, aldehyde oxidase (AOX) may contribute to atRA biosynthesis. 21 At present, the respective, depot-specific roles of these enzymes in modulating human adipose tissue atRA concentrations and vitamin A homeostasis are unknown. Further, the potential influence of body weight on atRA formation requires additional investigation.…”

Section: How Might This Change Clinical Pharmacology or Translational...mentioning

confidence: 99%

“…N 2 ] lysine were from Thermo Fisher Scientific (Waltham, MA) and used as internal standards (IS) for AOX, aldehyde dehydrogenase 1 family member A1 (ALDH1A1) and family member A2 (ALDH1A2) protein quantification. 21,22 Human recombinant ALDH1A1, ALDH1A2, and AOX were expressed and purified as described previously and used as quantification standards. 21…”

Section: Chemicals and Reagentsmentioning

confidence: 99%

“…The aldehyde dehydrogenase 1A (ALDH1A) family of enzymes, 16,17 also known as retinaldehyde dehydrogenases (RALDHs), are the predominant enzymes contributing to at RA biosynthesis in many tissues, but their expression varies among tissues, cell types, and with developmental stage 18–20 . In addition, aldehyde oxidase (AOX) may contribute to at RA biosynthesis 21 . At present, the respective, depot‐specific roles of these enzymes in modulating human adipose tissue at RA concentrations and vitamin A homeostasis are unknown.…”

Section: Introductionmentioning

confidence: 99%

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Evidence of depot‐specific regulation of all‐trans‐retinoic acid biosynthesis in human adipose tissue

Rubinow

Zhong

Czuba

et al. 2022

Clinical Translational Sci

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The prevalence of obesity continues to rise, underscoring the need to better understand the pathways mediating adipose tissue (AT) expansion. All-trans-retinoic acid (atRA), a bioactive vitamin A metabolite, regulates adipogenesis and energy metabolism, and, in rodent studies, aberrant vitamin A metabolism appears a key facet of metabolic dysregulation. The relevance of these findings to human disease is unknown, as are the specific enzymes implicated in vitamin A metabolism within human AT. We hypothesized that in human AT, family 1A aldehyde dehydrogenase (ALDH1A) enzymes contribute to atRA biosynthesis in a depot-specific manner. To test this hypothesis, parallel samples of subcutaneous and omental AT from participants (n = 15) were collected during elective abdominal surgeries to quantify atRA biosynthesis and key atRA synthesizing enzymes. ALDH1A1 was the most abundant ALDH1A isoform in both AT depots with expression approximately twofold higher in omental than subcutaneous AT. ALDH1A2 was detected only in omental AT. Formation velocity of atRA was approximately threefold higher (p = 0.0001) in omental AT (9.8 [7.6, 11.2]) pmol/min/mg) than subcutaneous AT (3.2 [2.1,4.0] pmol/min/mg) and correlated with ALDH1A2 expression in omental AT (β-coefficient = 3.07, p = 0.0007) and with ALDH1A1 expression in subcutaneous AT (β-coefficient = 0.13, p = 0.003). Despite a positive correlation between body mass index (BMI) and omental ALDH1A1 protein expression (Spearman r = 0.65, p = 0.01), BMI did not correlate with atRA formation.Our findings suggest that ALDH1A2 is the primary mediator of atRA formation in omental AT, whereas ALDH1A1 is the principal atRA-synthesizing enzyme in subcutaneous AT. These data highlight AT depot as a critical variable for defining the roles of retinoids in human AT biology.

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afe = 10^{\frac{1}{normaln} \sum normallog \frac{v_{predicted}}{v_{observed}}}

…”

Section: Methodsmentioning

confidence: 86%

Section: Methodsmentioning

confidence: 99%

Section: How Might This Change Clinical Pharmacology or Translational...mentioning

confidence: 99%

Section: Chemicals and Reagentsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Evidence of depot‐specific regulation of all‐trans‐retinoic acid biosynthesis in human adipose tissue

Rubinow

Zhong

Czuba

et al. 2022

Clinical Translational Sci

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A single-cell transcriptomic atlas characterizes liver non-parenchymal cells in healthy and diseased mice

Wang

Qian

et al. 2021

Preprint

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The heterogeneity of liver non-parenchymal cells (NPCs) is essential for liver structure and function. However, the current understanding of liver NPCs, especially in different liver diseases, remains incompletely elucidated. Here, a single-cell transcriptome atlas of 171,814 NPCs from healthy and 5 typical liver disease mouse models, including alcoholic liver disease, nonalcoholic steatohepatitis (NASH), drug-induced liver injury, cholestatic, and ischemia-reperfusion liver injury is constructed. The inter- and intra-group heterogeneity of 12 types (and numerous subtypes) of NPCs involving endothelial cells, hepatic stellate cells (HSCs), neutrophils, T cells, and mononuclear phagocytes (MPs) are summarized. A protective subtype of neutrophils characterized by Chil3high is validated and found significantly increasing only in drug-induced and cholestatic liver injury models. Transcriptional regulatory network analysis reveals disease-specific transcriptional reprogramming. Metabolic activity analysis indicates that fibrosis is accompanied by increases in glycolysis and retinol metabolism in activated HSCs and MPs. Moreover, we found that cell-cell interactions between cholangiocytes and immune cells contribute more to cholestatic liver fibrosis compared with NASH, while HSCs are more important for NASH fibrosis. Our atlas, together with an interactive website provides a systematic view of highly heterogeneous NPCs and a valuable resource to better understand pathological mechanisms underlying liver diseases.

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A9 - Aldehyde oxidase contributes to all-trans-retinoic acid biosynthesis in human liver

Cited by 2 publications

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Evidence of depot‐specific regulation of all‐trans‐retinoic acid biosynthesis in human adipose tissue

Evidence of depot‐specific regulation of all‐trans‐retinoic acid biosynthesis in human adipose tissue

A single-cell transcriptomic atlas characterizes liver non-parenchymal cells in healthy and diseased mice

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