Baat-Deficient Mice Recapitulate Elevated 7α-Hydroxy-3-Oxo-4-Cholestenoic Acid Observed in a Japanese Patient With...

Area of Science:

• Biochemistry
• Metabolic Disorders
• Genetics

Background:

• Bile acid Coenzyme A: amino acid N-acyltransferase (BAAT) is crucial for bile acid conjugation, impacting lipid absorption.
• BAAT mutations cause inborn errors, leading to reduced conjugated bile acids and vitamin deficiencies.
• Unexplained clinical features suggest broader metabolic disturbances beyond impaired conjugation.

Purpose of the Study:

• To investigate the metabolic consequences of BAAT deficiency.
• To identify novel metabolic disturbances associated with BAAT loss.
• To establish a relevant in vivo model for studying BAAT deficiency.

Main Methods:

• Serum bile acid and intermediate profiling in a patient with BAAT deficiency.
• Generation of a hepatic Baat knockdown mouse model using AAV-mediated CRISPR/Cas9.
• Integrated analyses including quantitative PCR and stable-isotope tracing.

Main Results:

• Identified elevated 7α-hydroxy-3-oxo-4-cholestenoic acid (7-HOCA) in a patient and the mouse model.
• Observed reduced amino acid-conjugated bile acids and increased 7-HOCA in Baat-deficient livers.
• Demonstrated enhanced cholesterol flux and upregulated bile acid synthesis enzymes in Baat-deficient livers.

Conclusions:

• BAAT deficiency causes dysregulated bile acid synthesis, not just defective conjugation.
• Reveals a previously unrecognized metabolic phenotype of BAAT deficiency.
• Establishes a novel in vivo model for studying bile acid metabolism beyond conjugation defects.