Pathway Preferential Estrogens Prevent Hepatosteatosis Due to Ovariectomy and High-Fat Diets

Abstract

About 20–30% of premenopausal women have metabolic syndrome, and the number is almost double in postmenopausal women, and these women have an increased risk of hepatosteatosis. Postmenopausal women with metabolic syndrome are often treated with hormone replacement therapy (HRT), but estrogens in currently available HRTs increase the risk of breast and endometrial cancers and Cardiovascular Disease. Therefore, there is a critical need to find safer alternatives to HRT to improve postmenopausal metabolic health. Pathway preferential estrogen 1 (PaPE−1) is a novel estrogen receptor ligand that has been shown to favorably affect metabolic tissues without adverse effects on reproductive tissues. In this study, we have examined the effects of PaPE−1 on metabolic health, in particular, examining its effects on the liver transcriptome and on plasma metabolites in two different mouse models: diet−induced obesity (DIO) and leptin−deficient (ob/ob) mice. PaPE−1 significantly decreased liver weight and lipid accumulation in both DIO and ob/ob models and lowered the expression of genes associated with fatty acid metabolism and collagen deposition. In addition, PaPE−1 significantly increased the expression of mitochondrial genes, particularly ones associated with the electron transport chain, suggesting an increase in energy expenditure. Integrated pathway analysis using transcriptomics and metabolomics data showed that PaPE−1 treatment lowered inflammation, collagen deposition, and pathways regulating fatty acid metabolism and increased metabolites associated with glutathione metabolism. Overall, our findings support a beneficial metabolic role for PaPE−1 and suggest that PaPE−1 may protect postmenopausal women from fatty liver disease without increasing reproductive cancer risk.

Emerging Evidence on Membrane Estrogen Receptors as Novel Therapeutic Targets for Central Nervous System Pathologies

“…Since the activation of mERα in the medial preoptic area appeared to decrease overnight food and water intake in ovariectomized female rats, mERs have been postulated to control ingestive behaviors that occur at least in part through interactions with mGluR [ 134 ]. This is in line with PaPE-1-induced activation of mERα/mERβ, which reduced body weight gain and fat accumulation in the adipose tissues (perigonadal, perirenal, and subcutaneous) of ovariectomized mice [ 98 ] and significantly decreased liver weight and lipid accumulation in diet-induced obesity or leptin-deficient obese mice [ 135 ]. In these last two models, PaPE-1 also lowered the expression of genes associated with fatty acid metabolism and collagen deposition [ 98 , 135 ].…”

“…This is in line with PaPE-1-induced activation of mERα/mERβ, which reduced body weight gain and fat accumulation in the adipose tissues (perigonadal, perirenal, and subcutaneous) of ovariectomized mice [ 98 ] and significantly decreased liver weight and lipid accumulation in diet-induced obesity or leptin-deficient obese mice [ 135 ]. In these last two models, PaPE-1 also lowered the expression of genes associated with fatty acid metabolism and collagen deposition [ 98 , 135 ]. Moreover, it has been shown that the activation of mERα along with the PI3K/Akt pathway enhances the anorectic action of apolipoprotein A-IV (apoA-IV), as evidenced by significantly increased Akt phosphorylation in response to E2-BSA [ 136 ].…”

17β-Estradiol (E2) Upregulates the ERα/SIRT1/PGC-1α Signaling Pathway and Protects Mitochondrial Function to Prevent Bilateral Oophorectomy (OVX)-Induced Nonalcoholic Fatty Liver Disease (NAFLD)

“…The signaling process between E 2 and downstream molecules is unknown. Pathway preferential estrogen 1 (PaPE-1) is a novel estrogen receptor ligand that has been shown to favorably affect metabolic functions [41]. Estrogen-related receptor alpha (ERRα) was reported to contribute to the sex disparity in NAFLD development by regulating hepatic triglyceride biosynthesis and VLDL assembly and secretion, providing a novel treatment target [42,43].…”

Per- and Polyfluoroalkyl Substance Exposure Combined with High-Fat Diet Supports Prostate Cancer Progression

“…Purified HFDs for our studies (F3282 diet, Bio-Serv, USA), meant to mimic the "Western diet", are high in butterfat (~42% Kcal from fat) and polysaccharide. This diet is commonly used in metabolic syndrome studies [28,32,33].…”