Hepatocyte Small Heterodimer Partner Mediates Sex-Specific Effects on Triglyceride Metabolism via Androgen Receptor in Male Mice

Abstract

Mechanisms of sex differences in hypertriglyceridemia remain poorly understood. Small heterodimer partner (SHP) is a nuclear receptor that regulates bile acid, glucose, and lipid metabolism. SHP also regulates transcriptional activity of sex hormone receptors and may mediate sex differences in triglyceride (TG) metabolism. Here, we test the hypothesis that hepatic SHP mediates sex differences in TG metabolism using hepatocyte-specific SHP knockout mice. Plasma TGs in wild-type males were higher than in wild-type females and hepatic deletion of SHP lowered plasma TGs in males but not in females, suggesting hepatic SHP mediates plasma TG metabolism in a sex-specific manner. Additionally, hepatic deletion of SHP failed to lower plasma TGs in gonadectomized male mice or in males with knockdown of the liver androgen receptor, suggesting hepatic SHP modifies plasma TG via an androgen receptor pathway. Furthermore, the TG lowering effect of hepatic deletion of SHP was caused by increased clearance of postprandial TG and accompanied with decreased plasma levels of ApoC1, an inhibitor of lipoprotein lipase activity. These data support a role for hepatic SHP in mediating sex-specific effects on plasma TG metabolism through androgen receptor signaling. Understanding how hepatic SHP regulates TG clearance may lead to novel approaches to lower plasma TGs and mitigate cardiovascular disease risk.

Ablation of IFNγ in myeloid cells suppresses liver inflammation and fibrogenesis in mice with hepatic small heterodimer partner (SHP) deletion

“…In hepatic SHP knockout mice, the mRNA levels of hepatic lipid receptors (Srarb1 and Vldlr) and cholesterol transporters (Abcg5/8) were upregulated ( Figure 7 D). In line with this, the increased liver lipid uptake associated with the downregulation of hepatic SHP has been reported by different groups [ 9 , 16 , 20 ]. It has been reported that the bile acid pool size in the liver can be enlarged in SHP knockout mice due to the lack of suppression of Cyp7a1 and/or Cyp8b1 expression [ 9 , 13 , 20 , 46 ].…”

“…SHP regulates sex hormonal signaling pathways by interacting with androgen receptors (AR) and estrogen receptors [ 7 , 8 ]. We previously demonstrated that liver SHP contributes to sex differences in blood TG levels in an AR-dependent manner [ 9 ]. SHP suppresses virus-mediated infection by repressing the transcription of type I interferon (IFN) [ 10 ].…”

Triglyceride and Triglyceride-Rich Lipoproteins in Atherosclerosis

“…Of importance, microsomal triglyceride transfer protein (MTP) plays a key role in the assembly of VLDL and CM via transporting the related lipids to apoB particles ( Iqbal et al, 2020 ). Furthermore, recent studies have demonstrated that CETP increases the production of VLDL-TG in response to estrogen treatment via enhancing the expression of nuclear receptor and small heterodimer partner in female CETP transgenic mice ( Palmisano et al, 2016 ; Palmisano et al, 2021 ). Therefore, some endogenous molecules, such as estrogen, mediate sex-specific modulation of TG metabolism.…”

Orphan receptors in prostate cancer

“…98 Overall, it interacts with several other nuclear receptors, including the AR. 97,99 Shp acts as a mediating factor in the metabolic circadian clock. 100 It has been suggested that some atypical retinoids can act as ligands to promote its activity.…”

“…Moreover, Shp intercepts with the DNA binding of nuclear receptors 98 . Overall, it interacts with several other nuclear receptors, including the AR 97,99 . Shp acts as a mediating factor in the metabolic circadian clock 100 .…”