The regulation of L-valine in hormone synthesis

L-valine, one of the essential branched-chain amino acids (BCAAs) in humans, does not directly participate in the structural composition of hormone molecules. However, it exerts indirect yet critical regulatory effects on the synthesis of various hormones by modulating metabolic pathways, signal transduction, and cellular microenvironments. This is particularly evident in the synthesis of steroid hormones, peptide hormones, and stress hormones, with distinct regulatory mechanisms as follows:

I. Supporting Substrate Supply for Steroid Hormone Synthesis via Metabolic Intermediates

Steroid hormones (e.g., glucocorticoids, sex hormones, mineralocorticoids) are synthesized using cholesterol as a precursor. L-valine metabolism provides key energy and material support for this process:

L-valine undergoes catabolism to produce succinyl-CoA, which enters the tricarboxylic acid (TCA) cycle, supplying NADPH (reducing equivalents) and acetyl-CoA (carbon skeletons) for cholesterol synthesis. Adequate L-valine availability enhances TCA cycle flux, ensuring sufficient cholesterol precursors to promote the synthesis of adrenal cortical hormones (e.g., cortisol) and gonadal hormones (e.g., testosterone, estradiol). Conversely, valine deficiency may reduce cholesterol precursors, limiting steroid hormone synthesis—for instance, in chronic malnutrition, adrenal cortex responsiveness to adrenocorticotropic hormone (ACTH) weakens, decreasing cortisol production.

Additionally, ATP generated from L-valine metabolism fuels enzymatic reactions in steroidogenesis, such as hydroxylation and oxidation. In adrenal cortical cells, cytochrome P450 enzymes (e.g., CYP11A1, CYP17A1) that catalyze cholesterol conversion are highly energy-dependent. Efficient valine metabolism maintains the activity of these rate-limiting enzymes, ensuring steady hormone synthesis.

II. Influencing Hormone Secretion via Regulation of Cellular Stress and Signaling Pathways

L-valine indirectly regulates hormone synthesis and secretion by modulating intracellular stress states and signaling molecule expression, particularly in stress hormones and metabolism-related hormones:

In the synthesis of stress hormones (e.g., cortisol), L-valine mitigates oxidative stress by maintaining intracellular glutathione (GSH) levels. Its metabolic intermediate, α-ketoisovalerate, participates in GSH synthesis; as an antioxidant, GSH protects adrenal cortical cells from reactive oxygen species (ROS) damage, ensuring activation of the ACTH receptor and downstream cAMP/PKA signaling pathways, thereby promoting cortisol synthesis and release. Valine deficiency impairs cellular antioxidant capacity, potentially reducing cortisol sensitivity to ACTH and disrupting the body’s stress response.

In pancreatic β-cells, L-valine acts as a signaling molecule to activate the mTORC1 pathway, stimulating insulin synthesis and secretion. Mechanistically, valine enters β-cells via transporters, activating amino acid-sensing pathways, upregulating transcription of the proinsulin gene (INS), and promoting exocytosis of insulin granules. Simultaneously, energy from valine metabolism enhances intracellular calcium influx, synergistically stimulating insulin release—a critical role during blood glucose fluctuations to maintain glycemic homeostasis.

III. Regulating Peptide Hormone Synthesis via Amino Acid Balance Maintenance

The synthesis of peptide hormones (e.g., growth hormone, insulin-like growth factor-1) depends on adequate amino acid supply and proportional balance. L-valine functions through two mechanisms:

As a raw material for protein synthesis, L-valine participates in the synthesis of hormone precursor peptides. For example, translation of growth hormone precursors requires BCAAs like valine; its deficiency directly hinders precursor peptide synthesis, reducing mature growth hormone secretion.

More importantly, L-valine maintains the balance of intracellular amino acid pools through synergistic interactions with other amino acids, preventing interference from excess or deficiency of individual amino acids. In the liver, for instance, growth hormone-induced insulin-like growth factor-1 (IGF-1) synthesis is supported by valine, which promotes stable IGF-1 mRNA expression. Imbalances in the ratio of valine to arginine or leucine may inhibit this process, reducing IGF-1 synthesis and impairing growth and metabolic regulation.

IV. Specificity and Synergy in Hormone Synthesis Regulation

L-valine’s regulatory effects exhibit tissue specificity: in the adrenal cortex, it primarily supports steroid hormone synthesis via metabolism; in pancreatic β-cells, it acts through signaling pathway activation; in the pituitary and liver, it focuses on substrate supply and balance maintenance. Additionally, its actions often synergize with other BCAAs (e.g., leucine, isoleucine). For example, all three enhance insulin secretion via the mTORC1 pathway, but valine uniquely supports steroid hormone synthesis through metabolic contributions.

L-valine indirectly but crucially regulates hormone synthesis through multidimensional mechanisms, including metabolic substrate supply, signaling pathway modulation, and amino acid balance maintenance. Abnormal valine levels may disrupt the homeostasis of steroid and peptide hormones, impacting stress responses, metabolic diseases, and growth. This regulatory network provides insights into the relationship between amino acids and hormonal balance, offering potential targets for nutritional interventions or drug development in related diseases.