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Osteocytes/Osteoblasts Produce SAA3 to Regulate Hepatic Metabolism of Cholesterol

Shijiang Huang1, Yuanjun Jiang1, Jing Li2

  • 1State Key Laboratory of Organ Failure Research, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|April 13, 2024
PubMed

Insights

Genetic depletion of tuberous sclerosis complex 1 (TSC1) in bone cells increases serum cholesterol. This is linked to serum amyloid A3 (SAA3) signaling, which impairs bile acid production in the liver.

Area of Science:

  • Biochemistry
  • Metabolic Diseases
  • Bone Biology

Background:

  • Hypercholesterolaemia is a systemic metabolic disease with underappreciated roles of non-hepatic organs.
  • The tuberous sclerosis complex 1 (TSC1) gene is crucial for cellular growth and metabolism.

Purpose of the Study:

  • To investigate the role of osteocyte/osteoblast-specific TSC1 depletion in cholesterol metabolism.
  • To elucidate the mechanism linking bone and liver in cholesterol regulation.

Main Methods:

  • Phenotypic characterization of Tsc1Dmp1 mice (osteocyte/osteoblast-specific TSC1 knockout).
  • Analysis of serum cholesterol, serum amyloid A3 (SAA3) levels, and hepatic gene expression (CYP7A1).
  • Investigated the interaction between SAA3 and toll-like receptor 4 (TLR4) signaling.

Main Results:

  • Genetic depletion of TSC1 in osteocytes/osteoblasts led to progressive hypercholesterolaemia.
  • Upregulation of bone and serum SAA3 was observed.
  • SAA3 from bone bound to TLR4 on hepatocytes, suppressing cholesterol 7 α-hydroxylase (CYP7A1) expression and bile acid synthesis.
  • Ablation of Saa3 in knockout mice normalized CYP7A1 expression and serum cholesterol.

Conclusions:

  • Bone plays a significant role in systemic cholesterol metabolism.
  • A novel pathway involving bone-derived SAA3, TLR4, and hepatic CYP7A1 regulates cholesterol homeostasis.
  • Pharmacological targeting of SAA3 presents a potential therapeutic strategy for hypercholesterolaemia.
Keywords:
CYP7A1SAA3bone‐liver crosstalkhypercholesterolaemiaosteocytes/osteoblasts

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