The transcription factor cyclic AMP–responsive element–binding protein H regulates triglyceride metabolism

The transcription factor CREB-H has been found to regulate the expression of a suite of genes in mice that are involved in triglyceride metabolism, according to a new study by Ann-Hwee Lee and her colleagues. They also find loss-of-function mutations in the human gene for CREB-H that are associated with highly elevated levels of triglycerides, suggesting a similar role for the protein in humans. Here we report that the transcription factor cyclic AMP–responsive element–binding protein H (CREB-H, encoded by CREB3L3 ) is required for the maintenance of normal plasma triglyceride concentrations. CREB-H–deficient mice showed hypertriglyceridemia secondary to inefficient triglyceride clearance catalyzed by lipoprotein lipase (Lpl), partly due to defective expression of the Lpl coactivators Apoc2 , Apoa4 and Apoa5 (encoding apolipoproteins C2, A4 and A5, respectively) and concurrent augmentation of the Lpl inhibitor Apoc3. We identified multiple nonsynonymous mutations in CREB3L3 that produced hypomorphic or nonfunctional CREB-H protein in humans with extreme hypertriglyceridemia, implying a crucial role for CREB-H in human triglyceride metabolism.