Hepatic ChREBP Drives Cardiac Remodeling via ApoM Non-transcriptional Repression

Background

Pathological cardiac remodeling is a hallmark of numerous cardiovascular diseases and develops into heart failure. As a systemic disease, effective treatments for cardiac remodeling from a tissue crosstalk perspective are still significantly unmet.

Methods

Hepatocyte-specific ChREBP (carbohydrate response element binding protein) knockout (KO) or overexpressed mice, global ApoM (apolipoprotein M) KO and adeno-associated virus-mediated hepatic ApoM knockdown or overexpressed mice, cardiomyocyte-specific ChREBP overexpressed mice, as well as S1PR1 (sphingosine-1-phosphate receptor 1) knockdown mice were used in isoproterenol- or transverse aortic constriction-induced cardiac remodeling models. RNA sequencing and liquid chromatography - tandem mass spectrometry (LC-MS/MS) analysis were used to detect changed pathways and the interaction between ChREBP and SURF4 (surfeit 4).

Results

We found increased ChREBP expression in the liver, but not in the heart, especially in the cytosol of hepatocytes, but not the nucleus, in isoproterenol- or transverse aortic constriction-induced mice. Hepatocyte-specific ChREBP deficiency protected against isoproterenol or transverse aortic constriction-induced cardiac remodeling. Mechanistically, hepatocyte ChREBP deficiency increased ApoM expression in the liver and its secretion, not by transcriptional regulation of ApoM, but by increasing its secretion through the release of SURF4. ApoM overexpression in the liver or ApoM-containing high-density lipoprotein (HDL) injection can both ameliorate cardiac remodeling through the S1P (sphingosine-1-phosphate)/S1PR1 pathway in the heart.

Conclusions

This work identifies the hepatic ChREBP-SURF4-ApoM axis as a critical pathway in cardiac remodeling, and induction of hepatic ApoM secretion constitutes a new promising approach for treating cardiac remodeling and heart failure.