TXNIP is a critical regulator of human cardiometabolic health

Thioredoxin interacting protein, encoded by TXNIP , is a key mediator of glucose and lipid metabolism in preclinical models. However, its role in human metabolism is not well understood. We have characterized a cohort of individuals with biallelic pathogenic variants in TXNIP who exhibit lactic acidosis, dyslipidemia, adult-onset severe cardiomyopathy, hypoglycemia, and skeletal muscle weakness. Mechanistically, TXNIP dysfunction was associated with increased fatty acid synthesis and complex rearrangements of the cellular lipidome and proteome. Restriction of dietary carbohydrates resulted in partial rescue of fatty acid synthesis markers and lipid storage in hearts of Txnip -KO mice, but led to dyslipidemia. Our studies show that TXNIP is an important modifier in cardiac and skeletal muscle as well as in lipoprotein metabolism and that biallelic pathogenic variants in TXNIP lead to a complex disease affecting cellular lipid metabolism of multiple organ systems with potentially fatal adult-onset cardiomyopathy.