HIF-driven SF3B1 induces KHK-C to enforce fructolysis and heart disease

Area of Science:

• Biochemistry
• Cardiology
• Molecular Biology

Background:

• Fructose is a key dietary sugar linked to metabolic syndrome.
• Ketohexokinase (KHK) metabolizes fructose, with isoforms KHK-A and KHK-C.
• KHK-C, with higher affinity, primarily metabolizes fructose in the liver.

Purpose of the Study:

• Investigate the role of myocardial fructose metabolism in pathological cardiac hypertrophy.
• Identify molecular mechanisms regulating fructose metabolism in the heart under hypoxic stress.

Main Methods:

• Utilized human and mouse models of pathological cardiac hypertrophy.
• Examined the effects of myocardial hypoxia, HIF1α activation, and SF3B1.
• Assessed the impact of SF3B1 depletion and Khk gene ablation in mice.

Main Results:

• Myocardial hypoxia induces fructose metabolism in the heart via HIF1α and SF3B1.
• SF3B1 mediates the splice switching of KHK-A to KHK-C in hypoxic conditions.
• Heart-specific SF3B1 depletion or Khk ablation mitigated stress-induced fructose metabolism, cardiac growth, and dysfunction.

Conclusions:

• SF3B1 is a critical regulator of fructose metabolism in the heart during pathological hypertrophy.
• This pathway highlights a novel fructose metabolism regulatory system crucial for pathological cardiac growth.