Signalling by Lipid Soluble Hormones

HUBS2206 Human Biochemistry and Cell Biology Lecture 30: Signalling by Lipid Soluble Hormones

Learning Targets

• Lipid-soluble hormones synthesis
• Lipid-soluble hormones release
• Hormonal control (HPA axis)
• How they induce a physiological response
  • Activation of intracellular receptors
  • Slow acting
• Focus on vitamin D, thyroid and steroid hormones

Key concept: Lipid-soluble hormones play an important role in adaptation of cells to changes in their environment.

Hormonal Signalling

• Water soluble hormones act on cell surface receptors (e.g. RTKs, GPCRs).
• Lipid soluble hormones act on intracellular receptors.

Lipid-Soluble Hormones

• Release, transport and mechanism of action.

Synthesis and Release

• Steroid hormones are derived from cholesterol.
• Thyroid hormones are derived from tyrosine (amino acid).
• Lipid-soluble hormones are made de novo in response to a stimulus and then released by simple diffusion as they are made.
  • No storage in vesicles occurs.
  • Not a regulated secretion.

Transport

• Hydrophobic nature means the majority of circulating hormones reversibly attach to carrier proteins.
  • Majority bound to hormone-specific carrier proteins.
  • Some bound to plasma albumin (= non-selective transporter).
• Transport functions:
  • Prolongs half-life of hormone (protects from enzymatic degradation, kidney filtration).
  • Serves as reservoir for hormones.
  • Facilitates distribution throughout vascular system.
• When bound to transporter, the hormone has no biological activity.
• Only a tiny amount of free, unbound hormone is active, capable of entering cell and binding to intracellular receptors.

Activation of Intracellular Receptors

• Free hormone enters cell by diffusion (passive or facilitated).
• Many target cells can be affected by lipid soluble hormones.
• Binding to intracellular receptors:
  • Cytoplasmic or nuclear.
  • Upon hormone binding, receptor activated.
  • Cytoplasmic hormone-receptor complex translocates to nucleus.
• Nuclear hormone-receptor complex affects gene transcription leading to changes (usually increase) in synthesis of specific proteins.
• Exert slow, long-term physiological changes.

Summary: Water- vs Lipid-Soluble Hormones

Case Studies

Case Study 1: Corticosteroids

• Patient with severe pneumonia receiving intravenous glucocorticoids, which are drugs similar to cortisol.

Glucocorticoids/Cortisol

• Adrenal gland cortex releases glucocorticoids (cortisol = major one in human) in response to prolonged stress.
• Lipid steroid hormones made from cholesterol.
• Transported in blood (Cortisol binding globulin, transcortin, albumin).
• Slow-acting:
  • Acts on intracellular receptors.
  • Full action requires several hours.
  • Compare with adrenaline: rapid response (fight or flight).

Effects on Gene Expression

• One signalling molecule binding to a receptor can cause a series of genes to be transcribed at a higher level, or can inhibit transcription.
• Effects of glucocorticoids:
  • Promote complex metabolic changes.
  • \uparrow expression of anti-inflammatory genes.
  • \downarrow expression of pro-inflammatory genes.
• Huge medical utilisation of man-made form (potent anti-inflammatory and immunosuppressive properties).
• Glucocorticoids can coordinate activation of different genes at once.

Case Study 2: Vitamin D

• Patient with hip fracture and osteoporosis and low vitamin D levels.

Vitamin D

• Some vitamin D in selected food (e.g. fish liver/oils, fatty fish, egg yolks).
• Most produced in the skin by photochemical synthesis (exposure of precursor to UVB radiation).
• Inactive pro-hormone.
• Must be metabolised in kidney to active form called calcitriol.
• Crucial function of calcitriol is to \uparrow Ca2+ absorption from the diet.

Vitamin D is a Hormone!

• Lipid-soluble steroid hormone.
• Transported in blood by vitamin D-binding protein.
  • Long half-life in plasma (5-12h).
• Calcitriol exerts action by binding to intracellular vitamin D receptors leading to gene expression and protein synthesis.
• Calcitriol controls synthesis of genes encoding proteins that increase calcium absorption from the small intestine.
• In the absence of vitamin D, dietary calcium is not efficiently absorbed.

Vitamin D is Important for Bone Health

• Calcitriol is slow-acting and maintains day-to-day control of serum calcium concentration.
  • Many other functions (immune system, reduced inflammation, muscle…).
• Calcium homeostasis essential for bone health.
  • Bone = Ca2+ reservoir.
  • \sim 99\% Ca2+ in bone to make and maintain skeleton.
  • Ca2+ liberated in blood if blood calcium drops.
• Very common vitamin D deficiency in population.
  • As much as > 40\% of world population -1 in 5 kids.
  • Reduced intake.
  • Age-related factors.
  • \downarrow sunlight exposure.
  • Decline in renal function…

Case Study 3: Thyroid Hormones

• Symptoms and signs of hyperthyroidism includes multiple widespread effects in the body.
• Increased metabolism: "hypermetabolic state".

How is Release of Thyroid Hormones Triggered?

• Hormonal stimulus:
  • Hypothalamus releases Thyroid Releasing Hormone (TRH).
  • TRH stimulates the pituitary gland to release Thyroid Stimulating Hormone (TSH).
  • TSH stimulates the thyroid gland.

Thyroid Hormones

• Lipid soluble hormones produced by thyroid follicle cells.
  • T4 and T3 (= biological active form).
  • T4 (thyroxine or tetraiodothyronine); T3 (tri-iodothyronine).
• TSH controls all steps of thyroid hormone synthesis and release.
  • Complex process!
• Thyrotropin-releasing hormone controls the release of TSH

Transport

• > 99\% of circulating thyroid hormone bound to carrier proteins.
  • Thyroxine-binding globulin (TBG)- most affinity
  • Albumin and thyroxine-binding prealbumine (TBPA, Transthyretin)

Mode of Action: Intracellular Receptors

• Cellular entry by diffusion or facilitated diffusion.
• Binding of of free active hormone to intracellular receptors leads to synthesis of proteins that control energy utilisation (lipid, fat and carb metabolism), cell growth and are essential for maturation of CNS.
• Also increase ATP production in mitochondria.
  • Leads to increase in basal metabolic rate.

The Nuclear Receptor Superfamily

• These nuclear receptors have a conserved DNA binding domain that allows them to function as transcription factors.
• The non-conserved regions generate the ligand- specific effects.
• Regulate numerous physiological processes such as metabolism, reproduction, inflammation

Thyroid Hormones – Feedback Mechanism

• Homeostasis: Since thyroid hormones have widespread and critical effects, levels must be tightly controlled.
• Constant state of adaptation.
• Feedback regulation by thyroid hormones.

What if Blood Thyroid Hormones Levels are Too Low?

• Negative feedback mechanisms regulate the blood levels of a large number of hormones!
• Critical role of Hypothalamus-pituitary axis.

Summary

• Lipid-soluble hormones play an important role in adaptation of cells to changes in their environment.
• Lipid-soluble hormones are made de novo in response to a stimulus and then released by simple diffusion as they are made.
• Circulating lipid-soluble hormones reversibly attach to carrier proteins.
• Lipid-soluble hormones bind to intracellular receptors.
• Key examples: vitamin D, thyroid and steroid hormones.
• Negative feedback loops regulate blood levels.