madman
Super Moderator
Abstract
Adipocytes express various enzymes, such as Aldo-keto reductases (AKR1C), 11β-hydroxysteroid dehydrogenase (11β-HSD), aromatase, 5α-reductases, 3β-HSD, and 17β-HSDs involved in steroid hormone metabolism in adipose tissues. Increased activity of AKR1C enzymes and their expression in mature adipocytes might indicate the association of these enzymes with subcutaneous adipose tissue deposition. The inactivation of androgens by AKR1C enzymes increases adipogenesis and fat mass, particularly subcutaneous fat. AKR1C also causes reduction of estrone, a weak estrogen, to produce 17β-estradiol, a potent estrogen, and, in addition, it plays a role in progesterone metabolism. Functional impairments of adipose tissue and imbalance of steroid biosynthesis could lead to metabolic disturbances. In this review, we will focus on the enzymes involved in steroid metabolism and fat tissue deposition.
Introduction
Adipose tissue constitutes an important site for steroid hormone synthesis, metabolism, and storage1-3.
Plasma dehydroepiandrosterone (DHEA), DHEA sulfate (DHEA-S), androstenedione, and testosterone are taken up and transformed into active hormones in adipose tissue by various steroid-converting enzymes4. The steroid biosynthetic pathway in adipose tissue depends on the relative expression or activity of steroidogenic enzymes4
Steroid metabolism involves the cytochrome P450 monooxygenases superfamily, Aldo-keto reductases (AKRs), short-chain dehydrogenase/reductase oxidoreductases, polyprenol reductases, uridine diphosphate glucuronosyl transferases, catechol-O-methyl transferases, sulfotransferases5-7, hydroxysteroid dehydrogenases (HSD), like 11β-HSD type 1, 11β-HSD type 2, 3β-HSD, 17β-HSDs, and aromatase (Figure 1). These enzymes are important for steroid biosynthesis and are expressed in preadipocytes and adipocytes8. In particular, the most important enzymes for the pathophysiology of adipose tissue are aldo-keto reductases, hydroxysteroid dehydrogenases (HSD), and aromatase, since they regulate the homeostasis of steroid hormones in the adipocytes9. In this review, we will focus on the enzymes involved in both steroid metabolism and fat tissue deposition.
*11β-Hydroxysteroid Dehydrogenase
*Aromatase
The ovaries and adipose tissue convert androstenedione and testosterone into estrogens through P450 aromatase activity. Aromatase activity is associated with body weight in both pre and post-menopausal females, and when knocked out17, both female and male mice show obesity with increased visceral fat17.
In adipose tissue, cytokines, including IL-6 and TNF-α, increase aromatase activity and transcription of the aromatase gene18. In opposition, a pulse of peroxisome proliferator-activated receptor-gamma agonist (PPARgA) to preadipocyte cultures of human breast cells decreases both transcription and activity of aromatase19. In the absence of PPARgA, subcutaneous abdominal preadipocyte expression of the P450 aromatase gene increases several days after induction of differentiation9,20.
*17β-Hydroxysteroid Dehydrogenases
*Glucocorticoid-Mediated Steroid Converting Enzymes
*Estrogen-Mediated Steroid Converting Enzymes
Estrogens, estradiol, estriol, and estrone, have a direct impact on adipose tissue metabolism and function27. Enzymes involved in estradiol synthesis also modulate local and whole-body estrogen availability28. Knockout mice for estrogen receptor α (ERα) have increased adiposity8. In agreement, variants in ER-α and ERβ encoding genes are associated with increased body fat mass and visceral fat accumulation in females. Moreover, low levels of estrogens might also stimulate preadipocyte proliferation, especially in females29,30. In white adipose tissue, lipid metabolism is regulated by estrogens through ERα, ERβ, and G protein coupled-estrogen receptors.
*Progesterone-Mediated Steroid Converting Enzymes
*Androgen-Regulated Steroid Converting Enzymes
*AKR1 Enzymes
*Role of AKR1C Enzymes
*Role of AKR1C in Subcutaneous Adipose Tissue (SAT) Accumulation
*AKR1C Enzymes in Androgen Metabolism
*Role of AKR1Cs in Androgen Activation/Inactivation
*AKR1Cs Effects on Neurosteroids
*AKR1C Effects on Urinary Metabolites
Conclusions
Adipose tissue is known to have endocrine properties and synthesize steroid metabolizing enzymes, like AKR1 enzymes, 11β-HSD, aromatase, and 17β-HSD. Adipose tissue is recognized as a substantial site for the action and transformation of steroid hormones. AKR1C enzymes are involved in the inactivation of androgen and progesterone which induces adipogenesis, and accumulation, proliferation, and differentiation of adipocytes. Genetic analyses have identified genes crucial for steroid metabolism that are linked with subcutaneous fat accumulation and lipedema74. These steroid-converting enzymes mediate the transformation of specific hormones into other hormones that are significantly involved in the metabolic pathways of adipose tissue. Further studies are required to elucidate the complexity of this enzymatic network and its multiple effects on adipose tissue functions.
Adipocytes express various enzymes, such as Aldo-keto reductases (AKR1C), 11β-hydroxysteroid dehydrogenase (11β-HSD), aromatase, 5α-reductases, 3β-HSD, and 17β-HSDs involved in steroid hormone metabolism in adipose tissues. Increased activity of AKR1C enzymes and their expression in mature adipocytes might indicate the association of these enzymes with subcutaneous adipose tissue deposition. The inactivation of androgens by AKR1C enzymes increases adipogenesis and fat mass, particularly subcutaneous fat. AKR1C also causes reduction of estrone, a weak estrogen, to produce 17β-estradiol, a potent estrogen, and, in addition, it plays a role in progesterone metabolism. Functional impairments of adipose tissue and imbalance of steroid biosynthesis could lead to metabolic disturbances. In this review, we will focus on the enzymes involved in steroid metabolism and fat tissue deposition.
Introduction
Adipose tissue constitutes an important site for steroid hormone synthesis, metabolism, and storage1-3.
Plasma dehydroepiandrosterone (DHEA), DHEA sulfate (DHEA-S), androstenedione, and testosterone are taken up and transformed into active hormones in adipose tissue by various steroid-converting enzymes4. The steroid biosynthetic pathway in adipose tissue depends on the relative expression or activity of steroidogenic enzymes4
Steroid metabolism involves the cytochrome P450 monooxygenases superfamily, Aldo-keto reductases (AKRs), short-chain dehydrogenase/reductase oxidoreductases, polyprenol reductases, uridine diphosphate glucuronosyl transferases, catechol-O-methyl transferases, sulfotransferases5-7, hydroxysteroid dehydrogenases (HSD), like 11β-HSD type 1, 11β-HSD type 2, 3β-HSD, 17β-HSDs, and aromatase (Figure 1). These enzymes are important for steroid biosynthesis and are expressed in preadipocytes and adipocytes8. In particular, the most important enzymes for the pathophysiology of adipose tissue are aldo-keto reductases, hydroxysteroid dehydrogenases (HSD), and aromatase, since they regulate the homeostasis of steroid hormones in the adipocytes9. In this review, we will focus on the enzymes involved in both steroid metabolism and fat tissue deposition.
*11β-Hydroxysteroid Dehydrogenase
*Aromatase
The ovaries and adipose tissue convert androstenedione and testosterone into estrogens through P450 aromatase activity. Aromatase activity is associated with body weight in both pre and post-menopausal females, and when knocked out17, both female and male mice show obesity with increased visceral fat17.
In adipose tissue, cytokines, including IL-6 and TNF-α, increase aromatase activity and transcription of the aromatase gene18. In opposition, a pulse of peroxisome proliferator-activated receptor-gamma agonist (PPARgA) to preadipocyte cultures of human breast cells decreases both transcription and activity of aromatase19. In the absence of PPARgA, subcutaneous abdominal preadipocyte expression of the P450 aromatase gene increases several days after induction of differentiation9,20.
*17β-Hydroxysteroid Dehydrogenases
*Glucocorticoid-Mediated Steroid Converting Enzymes
*Estrogen-Mediated Steroid Converting Enzymes
Estrogens, estradiol, estriol, and estrone, have a direct impact on adipose tissue metabolism and function27. Enzymes involved in estradiol synthesis also modulate local and whole-body estrogen availability28. Knockout mice for estrogen receptor α (ERα) have increased adiposity8. In agreement, variants in ER-α and ERβ encoding genes are associated with increased body fat mass and visceral fat accumulation in females. Moreover, low levels of estrogens might also stimulate preadipocyte proliferation, especially in females29,30. In white adipose tissue, lipid metabolism is regulated by estrogens through ERα, ERβ, and G protein coupled-estrogen receptors.
*Progesterone-Mediated Steroid Converting Enzymes
*Androgen-Regulated Steroid Converting Enzymes
*AKR1 Enzymes
*Role of AKR1C Enzymes
*Role of AKR1C in Subcutaneous Adipose Tissue (SAT) Accumulation
*AKR1C Enzymes in Androgen Metabolism
*Role of AKR1Cs in Androgen Activation/Inactivation
*AKR1Cs Effects on Neurosteroids
*AKR1C Effects on Urinary Metabolites
Conclusions
Adipose tissue is known to have endocrine properties and synthesize steroid metabolizing enzymes, like AKR1 enzymes, 11β-HSD, aromatase, and 17β-HSD. Adipose tissue is recognized as a substantial site for the action and transformation of steroid hormones. AKR1C enzymes are involved in the inactivation of androgen and progesterone which induces adipogenesis, and accumulation, proliferation, and differentiation of adipocytes. Genetic analyses have identified genes crucial for steroid metabolism that are linked with subcutaneous fat accumulation and lipedema74. These steroid-converting enzymes mediate the transformation of specific hormones into other hormones that are significantly involved in the metabolic pathways of adipose tissue. Further studies are required to elucidate the complexity of this enzymatic network and its multiple effects on adipose tissue functions.
