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Signalling by Lipid-Soluble Hormones

Learning Targets

• Understand how lipid-soluble hormones are synthesized.
• Understand how lipid-soluble hormones are released.
• Grasp the critical notion of hormonal control, particularly the HPA axis.
• Understand how lipid-soluble hormones induce a physiological response through the activation of intracellular receptors (slow-acting).
• Focus on specific examples: vitamin D, thyroid hormones, and steroid hormones.
• Key concept: Lipid-soluble hormones play a crucial role in adapting cells to environmental changes.

Hormonal Signalling

• Previous lectures covered water-soluble hormones acting on cell surface receptors (e.g., RTKs, GPCRs).
• This lecture focuses on intracellular receptors and lipid-soluble hormones.

Lipid-Soluble Hormones: Release, Transport, and Mechanism of Action

• Overview of the release, transport, and mechanism of action of lipid-soluble hormones.

Synthesis and Release

• Steroid hormones are derived from cholesterol.
• Thyroid hormones are derived from tyrosine (an amino acid).
• Lipid-soluble hormones are synthesized de novo (from scratch) in response to a stimulus and released via simple diffusion as they are made.
• They are not stored in vesicles and do not undergo regulated secretion.

Transport

• Due to their hydrophobic nature, most circulating hormones are reversibly bound to carrier proteins.
• The majority are bound to hormone-specific carrier proteins, while some bind to plasma albumin (a non-selective transporter).
• Functions of Transport:
  • Prolongs the hormone's half-life by protecting it from enzymatic degradation and kidney filtration.
  • Serves as a reservoir for hormones.
  • Facilitates distribution throughout the vascular system.
• Hormones bound to transporters have no biological activity; only the free, unbound hormone is active.
• Only a tiny amount of free, unbound hormone can enter cells and bind to intracellular receptors.

Activation of Intracellular Receptors

• Free hormone enters the cell via diffusion (passive or facilitated).
• Many target cells can be affected by lipid-soluble hormones.
• Hormones bind to intracellular receptors, which can be cytoplasmic or nuclear.
• Upon hormone binding, the receptor is activated.
• The cytoplasmic hormone-receptor complex translocates to the nucleus.
• The nuclear hormone-receptor complex affects gene transcription, usually increasing the synthesis of specific proteins.
• This process exerts slow, long-term physiological changes.

Summary: Water- vs. Lipid-Soluble Hormones

Case Studies

Case Study 1: Corticosteroids

• A patient with severe pneumonia is treated with antibiotics and intravenous glucocorticoids (similar to cortisol).

Glucocorticoids/Cortisol

• The adrenal gland cortex releases glucocorticoids (cortisol is the major one in humans) in response to prolonged stress.
• These are lipid steroid hormones made from cholesterol.
• Transported in the blood via cortisol-binding globulin, transcortin, and albumin.
• Slow-acting: act on intracellular receptors, with full action requiring several hours (compare to adrenaline's rapid response).

Effects on Gene Expression

• A single signaling molecule binding to a receptor can cause a series of genes to be transcribed at a higher level or inhibit transcription.
• Effects of Glucocorticoids:
  • Promote complex metabolic changes.
  • Increase (↑) expression of anti-inflammatory genes.
  • Decrease (↓) expression of pro-inflammatory genes.
• Man-made forms have significant medical use due to their potent anti-inflammatory and immunosuppressive properties (at high doses).
• Glucocorticoids can coordinate the activation of different genes simultaneously.

Case Study 2: Vitamin D

• An elderly woman with a hip fracture and osteoporosis is found to have low levels of vitamin D.

Vitamin D

• Some vitamin D is obtained from selected foods (e.g., fish liver/oils, fatty fish, egg yolks).
• Most vitamin D is produced in the skin via photochemical synthesis (exposure of a precursor to UVB radiation).
• It exists as an inactive pro-hormone that must be metabolized in the kidney to its active form, calcitriol.
• A crucial function of calcitriol is to increase (↑) Calcium ($Ca^{2+}$) absorption from the diet.

Vitamin D as a Hormone

• It is a lipid-soluble steroid hormone transported in blood by vitamin D-binding protein, with a long half-life in plasma (5-12 hours).
• Calcitriol exerts its action by binding to intracellular vitamin D receptors, leading to gene expression and protein synthesis.
• Calcitriol controls the 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 and Bone Health

• Calcitriol is slow-acting and maintains day-to-day control of serum calcium concentration.
• It has many other functions (immune system, reduced inflammation, muscle function).
• Calcium homeostasis is essential for bone health.
  • Bone serves as a calcium reservoir, containing approximately 99% of the body's calcium.
  • Calcium is liberated into the blood if blood calcium levels drop.
• Vitamin D deficiency is common, affecting a significant portion of the world population (e.g., >40% of the world population, 1 in 5 kids).
• Factors contributing to deficiency: reduced intake, age-related factors, decreased sunlight exposure, decline in renal function.

Case Study 3: Thyroid Hormones

Symptoms and Signs of Hyperthyroidism

• Multiple, widespread effects throughout the body due to increased metabolism (hypermetabolic state).
• Symptoms include hair loss, exophthalmos (protruding eyes), goiter, palpitations, anxiety, tremor, diarrhea, and weight loss.

Release of Thyroid Hormones

• Triggered by a hormonal stimulus: The hypothalamus releases thyrotropin-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: thyroxine (T4) and triiodothyronine (T3). T3 is the biologically active form.
• TSH controls all steps of thyroid hormone synthesis and release (a complex process!).
• TRH controls the release of TSH.

Transport

• Over 99% of circulating thyroid hormone is bound to carrier proteins:
  • Thyroxine-binding globulin (TBG) - highest affinity.
  • Albumin and thyroxine-binding prealbumin (TBPA, Transthyretin).

Mode of Action: Intracellular Receptors

• Cellular entry occurs via diffusion or facilitated diffusion.
• Binding of free active hormone to intracellular receptors leads to the synthesis of proteins that control energy utilization (lipid, fat, and carbohydrate metabolism), cell growth, and are essential for the maturation of the central nervous system (CNS).
• Also increases ATP production in mitochondria, leading to an 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.
• Non-conserved regions generate ligand-specific effects.
• Regulate numerous physiological processes such as metabolism, reproduction, and inflammation.

Thyroid Hormones – Feedback Mechanism

• Homeostasis: Thyroid hormone levels must be tightly controlled due to their widespread and critical effects.
• Regulation occurs through a constant state of adaptation and feedback regulation.

What if Blood Thyroid Hormone Levels Are Too Low?

• Decreased $T<em>3$ and $T</em>4$ concentrations in blood lead to the hypothalamus releasing TRH.
• TRH stimulates the pituitary gland to release TSH.
• TSH stimulates the thyroid gland to release $T<em>3$ and $T</em>4$.
• Increased $T<em>3$ and $T</em>4$ concentrations in blood suppress TRH and TSH production, restoring homeostasis.

Negative Feedback Mechanisms

• Negative feedback mechanisms regulate the blood levels of many hormones.
• The hypothalamus-pituitary axis plays a critical role.

Summary

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

Further Reading

• Alberts et al., Molecular Biology of the Cell, 6th edition: Chapter 15, Cell Signalling.