Evidence for a cardiometabolic sexual dimorphism in a non-obese mouse model of hepatic Lrpprc deficiency exhibiting microvesicular steatosis

Abstract

A recent meta-analysis showed that 20% of the world's population suffers from non-alcoholic fatty liver disease (NAFLD) without obesity. The progression of NAFLD involves cardiac manifestations, but the underlying mechanisms are not well established. Our objective is to characterize the cardiometabolic manifestations of NAFLD and evaluate the presence of a sexual dimorphism. The cardiac phenotype was investigated in a mouse model of hepatic Lrpprc deficiency (H-Lrpprc −/− ), as these mice develop microvesicular steatosis in absence of obesity and a NAFLD lipidomic profile secondary to mitochondrial bioenergetic deficiency. The cardiac repercussions were studied using molecular (qPCR, immunoblots), lipidomic (mass spectrometry) and functional (oximetry on isolated mitochondria) approaches. Loss of Lrpprc was specific to the liver and residual expression was similar in both sexes. In female mice, Lrpprc deficiency in the liver was associated with a decreased cardiac expression of gene markers for mitochondrial biogenesis (Tfam) and fusion (Mfn1-2), as well as genes related to fatty acid (FA) metabolism, including transcriptional regulator Pparα, FA transporters (Cd36, Cpt1b, Cpt2), and ß-oxidation enzymes (Vlcad, Lcad, Mcad). FA-dependent mitochondrial respiration was also reduced while cardiac triglyceride levels were elevated. In contrast, these alterations were almost completely absent in male mice. Collectively these results indicate that metabolic defects in the liver consequent to mitochondrial dysfunction in absence of obesity result in significant abnormalities in mitochondrial and metabolic phenotype of the heart, particularly in females, thus highlighting the existence of a major sexual dimorphism. This experimental model may prove useful to better understand the mechanisms underlying the sex-related variability in the progression of NAFLD in humans.