Caffeine Upregulates Hepatic Sex Hormone‐Binding Globulin Production by Increasing Adiponectin Through AKT/FOXO1 Pathway in White Adipose Tissue

Abstract

Scope Epidemiological studies have shown that caffeine increases serum sex hormone‐binding globulin (SHBG) levels. The relationship between caffeine and SHBG production has never been studied before at molecular level. The aim of this study is to examine whether caffeine regulates SHBG production and to determine the associated molecular mechanisms. Methods and results Two different studies are performed; in vitro studies using human HepG2 cells treated with caffeine (100 and 500 µm) and in vivo studies using a humanized SHBG transgenic mice drinking caffeine in the water (0.1 mg mL−1) for 12 days. The results show that caffeine does not change SHBG production in HepG2 cells. By contrast, caffeine treatment increases significantly hepatic SHBG production in human SHBG transgenic mice when compared with control mice. Caffeine increases adiponectin levels in epididymal adipose tissue of human SHBG transgenic mice. Moreover, caffeine increases adiponectin production by reducing protein kinase B (AKT) phosphorylation which increases forkhead box protein O1 (FOXO1) protein levels in 3T3‐L1 mature adipocytes and human SHBG transgenic mice. Finally, caffeine‐induced increase in adiponectin in turn upregulates hepatic hepatocyte nuclear receptor 4‐alpha (HNF‐4α) levels in human SHBG transgenic mice. Conclusions The results show that caffeine upregulates hepatic SHBG expression by increasing adiponectin production through AKT/FOXO1 pathway in the adipose tissue.

Caffeine in Hepatocellular Carcinoma: Cellular Assays, Animal Experiments, and Epidemiological Investigation

“…47 Moreover, the results of in vitro assays showed that caffeine (100 and 500 µM) has no significant effect on the protein production of sex hormone-binding globulin (SHBG) in HepG2 cells, while in vivo experiments found that humanized SHBG transgenic mice administered oral caffeine (0.1 mg/mL) for 12 days clearly improved hepatic SHBG production, induced an increase in adiponectin, and upregulated the level of hepatocyte nuclear factor 4-alpha in human SHBG transgenic mice, suggesting that caffeine mediates the progression of different liver diseases through multiple pathways. 48 Caffeine is well known to have several mechanisms of action, the most prominent of which is to bind reversibly to ARs, blocking their action. However, it is currently reported that caffeine has antioxidant and pro-oxidation properties, so more in-depth research is needed.…”

“…66 Moreover, caffeine solution (0.1 mg/mL) treatment for 12 days has been shown to significantly increase SHBG production in the liver and adiponectin levels in the epididymal adipose tissue of human SHBG transgenic mice. 48 Anti-fibrosis, anti-inflammatory, anti-infective, and anti-oxidant effects may explain the potential mechanism for the protective effect of caffeine on HCC induced by chemical poisons. Using macrophage-specific CD39 knockout mice, researchers found that cell-specific CD39 expression in macrophages and CD73 expression in HCC cells synergically activate the eATP-adenosine pathway, producing more adenosine, thereby impacting CD8 + T cell function and promoting anti-PD1 resistance, suggesting that targeted inhibition of adenosine alleviated HCC.…”

Molecular Mechanisms of Coffee on Prostate Cancer Prevention

“…Coffee compounds can decrease chronic inflammation and, therefore, protect against DNA degradation, consequently decreasing the risk of disease [46]. The Wistar rats A medium roast of Coffea arabica (+) SOD, CAT, and GPx [36] Wistar rats Green Coffea arabica (-) Lipid peroxidation (+) GSH, SOD, CAT, and GR [35] Wistar rats Green Coffea canephora and caffeine (-) Carrageenan-induced paw oedema (Pergolizzi et al 2018) Wistar rats Green Coffea arabica (-) IL-1β, TNF-α, and Nos2 (-) Interstitial inflammation index [47] Humanized SHBG transgenic mice Caffeine (+) Hepatic SHBG production (-) Akt phosphorylation [77] Cross-sectional clinical trial Caffeinated beverages Coffee consumption positively associated with SHBG concentration [78] Prospective clinical trial Caffeinated and decaffeinated coffee (-) CRP, IL-6, and TNFR-2 (+) Adiponectin and SHBG (-) Estrone (+) Testosterone (-) C-peptide and IGFBP-3 [50] Prospective clinical trial Coffee intake (-) Urinary 8-OHdG (-) Ferritin [61] Prospective clinical trial Coffee intake (+) AhR (+) CYP1A1/A2 [65] Intervention clinical trial Green and roasted Coffea arabica blend (-) Spontaneous DNA strand breaks ( [57]; 2014; 2011)…”

“…Decreased SHBG may be linked to an elevated risk of PCa [50]. Coffee and caffeine are linked to greater SHBG concentration [50,77,78]. Caffeine and SHBG are primarily metabolized by the liver, so one possible explanation is that caffeine intake might cause SHBG rise by impacting its catabolism [50].…”

“…Caffeine and SHBG are primarily metabolized by the liver, so one possible explanation is that caffeine intake might cause SHBG rise by impacting its catabolism [50]. Another possibility is that caffeine increases hepatic SHBG production by upregulation adiponectin synthesis and decreasing Akt phosphorylation [77].…”