Liver and Steroid Hormones—Can a Touch of p53 Make a Difference?

Liver and Steroid Hormones—Can a Touch of p53 Make a Difference?

Cite: Charni-Natan M, Aloni-Grinstein R, Osher E and Rotter V (2019) Liver and Steroid Hormones—Can a Touch of p53 Make a Difference? Front. Endocrinol. 10:374. doi: 10.3389/fendo.2019.00374

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General Information

Background

Liver:

© Charni 2019

Abstract

1. Liver serving as a hormonal secretory gland.
2. Steroid hormones is important
3. Liver is important to Steroid hormones homeostasis
4. P53 has impact on Liver
5. Hypothesis: P53-> Liver -> Steroid hormones -> Diseases
6. New way to diseases treatment (Maybe)

Introduction

P1: BG

Steroid hormones:

• reproductive
• metabolic homeostasis

Steroid hormones synthesis

• derived from cholesterol
• synthesized by adrenal cortex, gonads, and placenta.

Five groups: (based on nuclear receptor)^(1–5)

1. mineralocoriticoids
2. glucocorticoids
3. androgens
4. estrogens
5. progestogens

P53

• Responding for stress
• Regulating hormones expression

This discuss is focus on bidirectional relationship between different steroid hormones and liver and dependently on p53.

Steroid Hormones Homeostasis Regulation by the Liver

Cholesterol

Cholesterol Genesis⁽¹⁵⁾

• de-novo production
• hydrolysis of stored cholesterol
• interiorization of plasma membrane cholesterol
• from LDL and HDL

Metabolism

Metabolism^{(16, 17)}

• 5αR1 (liver enzyme 5α-reductase 1)
  • 5αR1-KO mice exhibited augmented mRNA levels of various hepatic metabolic regulators genes (e.g., Acc1, Agpat2, Cpt2, and Dgat2) in comparison to WT mice⁽¹⁸⁾.
• CYP (cytochromes P450 enzymes)
  • metabolism of many drugs and lipophilic compounds⁽¹⁹⁾
  • CYP3A4, CYP19, CYP2C2B1, and CYP2C11 are the liver CYPs and take part in steroid hormones hydroxylation and processing
  • CYP3A4^(20,21)
    • hydroxylases several steroids such as cortisol, androstenedione, testosterone, and progesterone
  • CYP19 (Aromatase)⁽¹⁰⁾
    • transforms androgens to estrogens by the removal of C19 carbon and the aromatization of the steroid A ring.
  • CYP2C11 and CYP2B1⁽¹⁰⁾
    • regulate hydroxylation of testosterone
  • Nuclear receptors complexes
    • NRC such as PXR, VDR, RXR were also found to bind CYP3A4 chromatin and affect its expression ^{(23, 24)}

Steroids Conjunction

• exerted by such as sulfotransferare and uridine diphosphate-glucuronosyltransferases (UGT)
  • ransfer the steroid hormones into higher polarity metabolites that are better suited to be excreted from the body⁽¹⁰⁾.
  • The sulfotransferases that are expressed by hepatic cells and are related to steroids conjugations are HSST, EST, SULT 2A1, and SULT 1E1 ⁽²⁵⁾.
  • be regulated by androgens, GCs, and nuclear receptors such as PXR⁽²⁷⁾.
• sulfotransferase inhibition
  • as well as EST KO, led to the acceleration of free steroids and thus to sexual abnormalities ^(10,26).

UGTs

• Two subfamilies
  • UGT2B
    • mainly expressed in the liver and is related the processing of steroid hormones⁽²⁸⁾.
• UGT
  • it induce glucuronidation of steroids, a process that interrupts steroids activity, and enables their elimination.
  • Tegulated by several xenobiotics compounds (e.g., PCN, PB), which were reported to increase their mRNA expression levels in rats’ livers ⁽²⁹⁾.

Transportation

As steroids, these hormones are lipophilic thus, when secreted into the blood stream they need to be bound to carrier proteins

• SHBG (Sex hormone binding globulin)
• CBG (Corticosteroid binding globulin)
• This carriers are glycoproteins which are mainly secreted by liver.^{(30, 31)}.
• Carrier proteins bind steroids and turn them to be biologically inactive ⁽³²⁾.
• effect different molecular pathways and signaling such as apoptosis ^{(33, 34)}
• Regulation:
  • factors such as glucose ⁽³⁵⁾, thyroid hormone < id="b_p18"sup>(36), and other factors such as the hepatocyte nuclear factor 4α (HNF-4α) ⁽³⁷⁾, PPAR-γ ⁽³⁸⁾, and p53 ⁽¹⁴⁾.

Glucocorticoids (GC)

Glucocorticoids are vital endocrine regulators of homeostasis and adaptation to environmental variations.
potent anti-inflammatory and immunosuppressive agents⁽⁴⁰⁾

• Cortisol⁽⁴²⁾
  • a main glucocorticoid secreted by the adrenal cortex
  • essential for immune system, vascular tone maintance
  • etc
    Played a major role during stress and severe illness by increasing cardiac output and vascular tonus and decreasing pro-inflammatory cytokines release^(43,44)
  • under the control of: ⁽⁴²⁾
    • HPA (hypothalamus-pituitary-adrenal )
    • ACTH (adrenocorticotropic hormone)
    • CRH (corticotropin-releasing hormone)
    • low-density lipoproteins (LDL) cholesterol insufficiency impair the production of cortisol ⁽⁴⁵⁾

NAFLD (Non-alcoholic fatty liver disease)

Metabolic disorder, characterized by hepatic steatosis, the presence of free fatty acids or triglycerides in the liver⁽⁴⁶⁾.

• Mice:
  • high fat diets & chronically elevated GC⁽⁴⁷⁾
• Patients:
  • elevated GC levels⁽⁴⁸⁾

(Skip)

Mineralocorticoids

synthesized by the adrenal cortex that influence salt and water balance.

(Skip)

Androgens

Androgens are the principal male sex hormones that regulated masculinizing (雄性化作用) effects and male sexual behavior.

• DHT(dehydroepiandrosterone)
  • it can bind androgen receptor(AR) as well as testosterone(82)

Estrogens

Estrogens are female principal sex hormone.

• E2 (17β estradiol) is essential for human

…

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