Dysfunction of estrogen-related receptor alpha-dependent hepatic VLDL secretion contributes to sex disparity in NAFLD/NASH development

Abstract

Rationale: Men and postmenopausal women are more prone to developing non-alcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) than premenopausal women. However, the pathological links and underlying mechanisms of this disparity are still elusive. The sex-difference in hepatic very low-density lipoprotein (VLDL) assembly and secretion may contribute to NAFLD development. Estrogen-related receptor alpha (ERRα) is a key regulator of several metabolic processes. We hypothesized that ERRα plays a role contributing to the sex-difference in hepatic VLDL assembly and secretion. Methods: VLDL secretion and essential genes governing said process were assessed in male and female mice. Liver-specific ERRα-deficient (ERRαLKO) mice were generated to assess the rate of hepatic VLDL secretion and alteration in target gene expression. Overexpression of either microsomal triglyceride transfer protein ( Mttp ) or phospholipase A2 G12B ( Pla2g12b ) by adenovirus was performed to test if the fatty liver phenotype in male ERRαLKO mice was due to defects in hepatic VLDL secretion. Female ERRαLKO mice were put on a diet high in saturated fat, fructose and cholesterol (HFHC) to promote NASH development. Wild type female mice were either ovariectomized or treated with tamoxifen to induce a state of estrogen deficiency or disruption in estrogen signaling. Adenovirus was used to overexpress ERRα in these mice to test if ERRα was sufficient to rescue the suppressed VLDL secretion due to estrogen dysfunction. Finally, wild type male mice on a high-fat diet (HFD) were treated with an ERRα inverse agonist to assess if suppressing ERRα activity pharmacologically would lead to fatty liver development. Results: ERRα is an indispensable mediator modulating hepatic triglyceride-rich very low-density lipoprotein (VLDL-TG) assembly and secretion through coordinately controlling target genes apolipoprotein B ( Apob ), Mttp and Pla2g12b in a sex-different manner. Hepatic VLDL-TG secretion is blunted in ERRαLKO mice, leading to hepatosteatosis which exacerbates endoplasmic reticulum stress and inflammation paving ways for NASH development. Importantly, ERRα acts downstream of estrogen/ERα signaling in contributing to the sex-difference in hepatic VLDL secretion effecting hepatic lipid homeostasis. Conclusions: Our results highlight ERRα as a key mediator which contributes to the sex disparity in NAFLD development, suggesting that selectively restoring ERRα activity in the liver may be a novel strategy for treating NAFLD/NASH.

Impact of liver-specific GLUT8 silencing on fructose-induced inflammation and omega oxidation

“…In this context, several studies indicate that this disparity is due to the preventive role of estrogen in hepatic steatosis (Chukijrungroat et al, 2017) among other mechanisms. Accordingly, recent studies have showed that higher hepatic estrogen-related receptor a expression in female mice contributes to the sex disparity in the assembly and secretion of hepatic triglyceride (TG)-rich very low-density lipoproteins (Yang et al, 2020). Interestingly, despite females being at lower risk of NAFLD development when comparing with males (Balakrishnan et al, 2020;Lonardo et al, 2019), rodent data support the idea that this risk can increase when liver damage is mediated by fructose intake (Choi et al, 2017;Hyer et al, 2019;Spruss et al, 2012).…”

Engineering stem cells to produce exosomes with enhanced bone regeneration effects: an alternative strategy for gene therapy

“…Cells between passages three and ten were used and propagated in α-MEM (Gibco, USA) supplemented with 20% fetal bovine serum (FBS, Gibco, USA) and 1% penicillin–streptomycin (Gibco, USA). Mouse hepatocytes were isolated from 8 weeks old male C57 mice, and cultured in L-DMEM (Hyclone, USA) containing 10% FBS and 2% penicillin–streptomycin [ 61 ]. Cells were maintained in a humidified atmosphere containing 95% air and 5% CO 2 at 37 °C.…”

Role of Steroid Hormones in the Pathogenesis of Nonalcoholic Fatty Liver Disease

“…For example, ERα-deficient mice have disrupted lipid metabolism, such as decreased fatty-acid oxidation and increased de novo lipogenesis, leading to elevated lipid accumulation in the liver compared with normal mice [ 70 , 71 , 72 ]. Similarly, downstream blocking of ERα contributed to higher visceral fat accumulation and reduced energy expenditure in female mice [ 34 , 70 , 73 ]. Meanwhile, E2 treatment promoted fatty-acid oxidation in the liver by increasing the expression of the fatty-acid transport protein, carnitine palmitoyltransferase 1 (CPT-1) [ 34 ].…”