Cholesteryl ester transfer protein alters liver and plasma triglyceride metabolism through two liver networks in female mice

Palmisano, Brian T.; Le, Thao D. V.; Zhu, Lin; Lee, Yoon Kwang; Stafford, John M.

doi:10.1194/jlr.m069013

Cited by 33 publications

(71 citation statements)

References 56 publications

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“…As expected, loss of liver ERα results in increased expression of lipid synthesis genes (Bryzgalova et al 2006), loss of estrogen regulation of target genes (Palmisano et al 2016; Zhu et al 2013), and impaired estrogen regulation of other lipid metabolic target genes (Della Torre et al 2016). One proposed mechanism for ERα regulation of lipid synthesis targets involves estrogen-ERα regulation of the nuclear receptor Small Heterodimer Partner (SHP), a target gene of ERα (Palmisano et al 2016; Wang et al 2015). Additionally, estrogen-ERα regulation of liver lipid metabolism has been proposed to act via microRNA mir-125b (Zhang et al 2015).…”

Section: Estrogens and The Physiologic Regulation Of Liver Lipid Metasupporting

confidence: 64%

“…Della Torre and colleagues demonstrated a requirement for liver ERα in mediating amino acid regulation of the reproductive cycle (Della Torre et al 2011). Using a mouse model with ERα-deficiency in hepatocytes, we demonstrated that the ability of estrogens to reduce liver steatosis is lost in with deletion of liver ERα, suggesting that estrogens are acting directly in liver to reduce TG content through ERα (Palmisano et al 2016; Zhu et al 2013; Villa et al 2012). As expected, loss of liver ERα results in increased expression of lipid synthesis genes (Bryzgalova et al 2006), loss of estrogen regulation of target genes (Palmisano et al 2016; Zhu et al 2013), and impaired estrogen regulation of other lipid metabolic target genes (Della Torre et al 2016).…”

Section: Estrogens and The Physiologic Regulation Of Liver Lipid Metamentioning

confidence: 99%

“…Using a mouse model with ERα-deficiency in hepatocytes, we demonstrated that the ability of estrogens to reduce liver steatosis is lost in with deletion of liver ERα, suggesting that estrogens are acting directly in liver to reduce TG content through ERα (Palmisano et al 2016; Zhu et al 2013; Villa et al 2012). As expected, loss of liver ERα results in increased expression of lipid synthesis genes (Bryzgalova et al 2006), loss of estrogen regulation of target genes (Palmisano et al 2016; Zhu et al 2013), and impaired estrogen regulation of other lipid metabolic target genes (Della Torre et al 2016). One proposed mechanism for ERα regulation of lipid synthesis targets involves estrogen-ERα regulation of the nuclear receptor Small Heterodimer Partner (SHP), a target gene of ERα (Palmisano et al 2016; Wang et al 2015).…”

Section: Estrogens and The Physiologic Regulation Of Liver Lipid Metamentioning

confidence: 99%

“…Additionally, a chemical model of menopause created by administration of 4-vinylcyclohexene diepoxide (VCD), which depletes primordial follicles, creates insulin resistance, fatty liver and dyslipidemia (Romero-Aleshire et al 2009). In addition to estrogen deficiency causing steatosis in rodent models, estrogen replacement reduces steatosis (Barrera et al 2014; Bryzgalova et al 2008; Villa et al 2012; Camporez et al 2013; Chambliss et al 2016; Palmisano et al 2016; Wang et al 2015; Zhu et al 2013; Kim et al 2014). …”

Section: Lack Of Estrogen Signaling Promotes Liver Tg Accumulation Anmentioning

confidence: 99%

“…Cholesterol feeding, insulin and ovarian hormones, all lead to significant changes in CETP activity (Arii et al 1997; Marotti et al 1993; Johansson et al 2012). Our recent work demonstrated that CETP is required for mice to increase plasma TGs in response to E2 treatment after ovariectomy (Palmisano et al 2016). CETP is a secreted plasma protein that shuttles TG and cholesteryl ester between plasma lipoproteins.…”

Section: Mouse-human Differences In Estrogen-regulated Liver Lipid Mementioning

confidence: 99%

See 4 more Smart Citations

Role of Estrogens in the Regulation of Liver Lipid Metabolism

Palmisano

Zhu

Stafford

2017

Sex and Gender Factors Affecting Metabolic Homeostasis, Diabetes and Obesity

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315

231

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Before menopause, women are protected from atherosclerotic heart disease associated with obesity relative to men. Sex hormones have been proposed as a mechanism that differentiates this risk. In this review, we discuss the literature around how the endogenous sex hormones and hormone treatment approaches after menopause regulate fatty acid, triglyceride and cholesterol metabolism to influence cardiovascular risk. The important regulatory functions of estrogen signaling pathways with regard to lipid metabolism have been in part obscured by clinical trials with hormone treatment of women after menopause, due to different formulations, routes of delivery, and pairings with progestins. Oral hormone treatment with several estrogen preparations increase VLDL triglyceride production. Progestins oppose this effect by stimulating VLDL clearance in both humans and animals. Transdermal estradiol preparations do not increase VLDL production or serum triglycerides. Many aspects of sex-differences in atherosclerotic heart disease risk are influenced by the distributed actions of estrogens in muscle, adipose and liver. In humans, 17β estradiol (E2) is the predominant circulating estrogen, and signals through Estrogen Receptor alpha (ERα), Estrogen Receptor beta (ER β) and G-protein coupled Estrogen Receptor (GPER). Over 1000 human liver genes display a sex-bias in their expression, and the top biological pathways are in lipid metabolism and genes related to cardiovascular disease. Many of these genes display variation depending on estrus cycling in the mouse. Future directions will likely rely on targeting estrogens to specific tissues, or specific aspects of the signaling pathways in order to recapitulate the protective physiology of pre-menopause therapeutically after menopause.

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Section: Estrogens and The Physiologic Regulation Of Liver Lipid Metasupporting

confidence: 64%

Section: Estrogens and The Physiologic Regulation Of Liver Lipid Metamentioning

confidence: 99%

Section: Estrogens and The Physiologic Regulation Of Liver Lipid Metamentioning

confidence: 99%

Section: Lack Of Estrogen Signaling Promotes Liver Tg Accumulation Anmentioning

confidence: 99%

Section: Mouse-human Differences In Estrogen-regulated Liver Lipid Mementioning

confidence: 99%

See 3 more Smart Citations

Role of Estrogens in the Regulation of Liver Lipid Metabolism

Palmisano

Zhu

Stafford

2017

Sex and Gender Factors Affecting Metabolic Homeostasis, Diabetes and Obesity

Self Cite

315

231

View full text Add to dashboard Cite

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Cholesteryl Ester Transfer Protein Impairs Triglyceride Clearance via Androgen Receptor in Male Mice

Palmisano

Anozie

et al. 2020

Lipids

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Elevated postprandial triacylglycerols (TAG) are an important risk factor for cardiovascular disease. Men have higher plasma TAG and impaired TAG clearance compared to women, which may contribute to sex differences in risk of cardiovascular disease. Understanding mechanisms of sex differences in TAG metabolism may yield novel therapeutic targets to prevent cardiovascular disease. Cholesteryl ester transfer protein (CETP) is a lipid shuttling protein known for its effects on high-density lipoprotein (HDL) cholesterol levels. Although mice lack CETP, we previously demonstrated that transgenic CETP expression in female mice alters TAG metabolism. The impact of CETP on TAG metabolism in males, however, is not well understood. Here, we demonstrate that CETP expression increases plasma TAG in males, especially in very-low density lipoprotein (VLDL), by impairing postprandial plasma TAG clearance compared to wild-type (WT) males. Gonadal hormones were required for CETP to impair TAG clearance, suggesting a role for sex hormones for this effect. Testosterone replacement in the setting of gonadectomy was sufficient to restore the effect of CETP on TAG. Lastly, liver androgen receptor (AR) was required for CETP to increase plasma TAG. Thus, expression of CETP in males raises plasma TAG by impairing TAG clearance via testosterone signaling to AR. Further understanding of how CETP and androgen signaling impair TAG clearance may lead to novel approaches to reduce TAG and mitigate risk of cardiovascular disease.

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Psoralen induces liver injury and affects hepatic bile acids metabolism in female and male C57BL/6J mice

Chen

Wang

Meng

et al. 2023

Phytotherapy Research

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Psoralen is a major component of Fructus Psoraleae that could induce liver injury. In this study, C57BL/6J mice were administered with psoralen at doses of 80 mg/kg for 3, 7 and 14 days. Blood and liver samples were collected for serum biochemistry and histopathology examinations, respectively. Psoralen led to liver injury with significantly increased liver weight and liver coefficient and up regulated serum ALT, AST and TG but down regulated serum TC and TP. The expression of bile acid-associated transporters and enzymes was detected by western blot, and the results showed that psoralen significantly down-regulates the expressions of CYP7A1, CYP27A1, BSEP and OSTα protein while up-regulates the expressions of HMGCR and FASN, resulting in the obstacles of bile acid efflux in the liver. The contents of 24 kinds of bile acids in the liver were measured by LC-MS/MS, and the results showed that psoralen led to the accumulation of unconjugated bile acids in the liver, such as ALCA and CA, which were more severe in male mice than female mice. It was indicated that psoralen may disrupt the balance of bile acid metabolism by inhibiting the expression of the efflux transporter, which then leads to liver damage.

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Cholesteryl ester transfer protein alters liver and plasma triglyceride metabolism through two liver networks in female mice

Cited by 33 publications

References 56 publications

Role of Estrogens in the Regulation of Liver Lipid Metabolism

Role of Estrogens in the Regulation of Liver Lipid Metabolism

Cholesteryl Ester Transfer Protein Impairs Triglyceride Clearance via Androgen Receptor in Male Mice

Psoralen induces liver injury and affects hepatic bile acids metabolism in female and male C57BL/6J mice

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