Sex Differences in Nonalcoholic Fatty Liver Disease: Estrogen Influence on the Liver–Adipose Tissue Crosstalk

Morán-Costoya, Andrea; Proenza, Ana M.; Gianotti, Magdalena; Lladó, Isabel; Valle, Adamo

doi:10.1089/ars.2021.0044

Cited by 31 publications

(25 citation statements)

References 196 publications

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“…Other research showing data from 488 postmenopausal women summarized that the duration of menopause directly impacts the severity of liver disease with increased risk of hepatic fibrosis or even hepatocarcinoma [2]. As estrogen directly influences energy homeostasis [3], hormone replacement therapy (HRT) has been utilized as a treatment for preventing postmenopausal women from developing lipid disorders [4]. However, it is still controversial whether HRT might be associated with an increased risk of breast and endometrial cancers [5,6].…”

Section: Introductionmentioning

confidence: 99%

Genistein Regulates Lipid Metabolism via Estrogen Receptor β and Its Downstream Signal Akt/mTOR in HepG2 Cells

et al. 2021

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Genistein (GEN) has been shown to significantly inhibit hepatic triglyceride accretion triggered by estrogen deficiency. The main purpose of this in vitro study was to investigate the function and molecular mechanism of estrogen receptor β (ERβ) in regulating hepatic lipid metabolism induced by GEN. Different doses of GEN or GEN with an ERβ antagonist were treated with HepG2 cells. Results showed that 25 μM GEN significantly diminished triglyceride levels. Meanwhile, GEN downregulated the levels of genes and proteins involved in lipogenesis, such as sterol-regulatory element-binding protein-1c (SREBP-1c), fatty acid synthase (FASN), and stearoyl-coenzyme A desaturase 1 (SCD1), and upregulated the gene and protein levels of the regulation factors responsible for fatty acid β-oxidation, such as carnitine palmitoyltransferase 1α (CPT-1α) and peroxisome proliferator-activated receptor α (PPARα). Furthermore, 25 μM GEN reduced the levels of phosphorylation of protein kinase B (Akt) and mechanistic target of rapamycin (mTOR). Moreover, most of these effects from GEN were reverted by pretreatment with the antagonist of ERβ. In conclusion, GEN improved hepatic lipid metabolism by activating ERβ and further modulation of Akt/mTOR signals. The results provide novel aspects of the regulatory mechanism of ERβ on hepatic lipid metabolism and might help to profoundly understand the functions of food-derived phytoestrogens in preventing and treating hepatic steatosis in postmenopausal women.

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Section: Introductionmentioning

confidence: 99%

Genistein Regulates Lipid Metabolism via Estrogen Receptor β and Its Downstream Signal Akt/mTOR in HepG2 Cells

et al. 2021

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“…The design of this study used ad libitum feeding of a recognized obesogenic diet formulation that induces both MAFLD as well as obesity in C57BL6/J mice since that is the human context in which our study questions are most appropriately considered. Figure 1 , Figure 2 and Figure 3 clearly show that excessive hepatic steatosis—a hallmark of MAFLD [ 8 , 27 , 63 ]—is prevented by common bean consumption regardless of sex. Such an effect only becomes uniform enough to achieve statistical significance in female mice when ≥ 35% of dietary protein is derived from bean.…”

Section: Discussionmentioning

confidence: 99%

“…Bean doses were calculated as 0% (bean-free control), 17.5%, 35%, and 70% of total dietary protein derived from bean. Total dietary fiber concentration of bean was 23.5 g/100 g bean powder [ 27 ]. The formulation of the experimental diets is shown in Supplemental Table S1 .…”

Section: Methodsmentioning

confidence: 99%

Thwarting Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) with Common Bean: Dose- and Sex-Dependent Protection against Hepatic Steatosis

et al. 2023

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Hepatic steatosis signifies onset of metabolic dysfunction-associated fatty liver disease (MAFLD) caused by disrupted metabolic homeostasis compromising liver function. Regular consumption of common beans reduces the risk of metabolic impairment, but its effective dose, the impact of biological sex, and underlying mechanisms of action are unknown. We fed female and male C57BL6/J mice with obesogenic yet isocaloric diets containing 0%, 17.5%, 35%, and 70% of total dietary protein derived from cooked whole common beans. Liver tissue was collected for histopathology, lipid quantification, and RNA-seq analyses. Beans qualitatively and quantitatively diminished hepatic fat deposition at the 35% dose in female and 70% dose in male mice. Bean-induced differentially expressed genes (DEGs) most significantly mapped to hepatic steatosis and revealed dose-responsive inhibition of de novo lipogenesis markers (Acly, Acaca, Fasn, Elovl6, Scd1, etc.) and triacylglycerol biosynthesis, activation of triacylglycerol degradation, and downregulation of sterol regulatory element-binding transcription factor 1 (SREBF1) signaling. Upregulated fatty acid β-oxidation was more prominent in females, while suppression of Cd36-mediated fatty acid uptake—in males. Sex-dependent bean effects also involved DEGs patterns downstream of peroxisome proliferator-activated receptor α (PPARα) and MLX-interacting protein-like (MLXIPL). Therefore, biological sex determines amount of common bean in the diet required to prevent hepatic lipid accumulation.

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“…While the mechanisms underlying the association between long or irregular menstrual cycles and NAFLD are unclear, exposure to estrogen may contribute to this association. Low 17β-estradiol levels, as well as the use of antiestrogens such as tamoxifen and aromatase inhibitors, have been associated with NAFLD (52). In contrast, estrogen replacement therapy has been reported to decrease the risk of NAFLD, which is reportedly twice as common in postmenopausal women than in premenopausal women (52,53).…”

Section: Discussionmentioning

confidence: 99%

Long or Irregular Menstrual Cycles and Risk of Prevalent and Incident Nonalcoholic Fatty Liver Disease

Cho

Chang

Kang

et al. 2022

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context The association of menstrual cycle length and irregularity with the risk of non-alcoholic fatty liver disease (NAFLD) is unknown. Objective We examined this association in large cross-sectional and cohort studies. Methods The cross-sectional study included 72 092 women younger than 40 years who underwent routine health examinations; the longitudinal analysis included the subset of 51 118 women without NAFLD at baseline. Long or irregular cycles were defined as menstrual cycles of 40 days or longer or too irregular to estimate. Abdominal ultrasonography was performed to identify NAFLD. Multivariable Cox proportional hazard regression analyses were performed to estimate hazard ratios (HRs) and 95% CIs for incident NAFLD according to menstrual cycle regularity and length, with 26- to 30-day cycles as the reference. Results At baseline, 27.7% had long or irregular menstrual cycles and 7.1% had prevalent NAFLD. Long or irregular menstrual cycles were positively associated with prevalent NAFLD. During a median follow-up of 4.4 years, incident NAFLD occurred in 8.9% of women. After adjustment for age, body mass index, insulin resistance, and other confounders, the multivariable-adjusted HR for NAFLD comparing long or irregular menstrual cycles to the reference group was 1.22 (95% CI, 1.14-1.31); this association strengthened in the time-dependent analysis with an HR of 1.49 (95% CI, 1.38-1.60). Conclusion Long or irregular menstrual cycles were associated with increased risk of both prevalent and incident NAFLD in young, premenopausal women. Women with long or irregular menstrual cycles may benefit from lifestyle modification advice to reduce the risk of NAFLD and associated cardiometabolic diseases.

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Sex Differences in Nonalcoholic Fatty Liver Disease: Estrogen Influence on the Liver–Adipose Tissue Crosstalk

Cited by 31 publications

References 196 publications

Genistein Regulates Lipid Metabolism via Estrogen Receptor β and Its Downstream Signal Akt/mTOR in HepG2 Cells

Genistein Regulates Lipid Metabolism via Estrogen Receptor β and Its Downstream Signal Akt/mTOR in HepG2 Cells

Thwarting Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) with Common Bean: Dose- and Sex-Dependent Protection against Hepatic Steatosis

Long or Irregular Menstrual Cycles and Risk of Prevalent and Incident Nonalcoholic Fatty Liver Disease

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