DHEA and Its Metabolites Reduce the Cytokines Involved in the Inflammatory Response and Fibrosis in Primary Biliary Cholangitis

Abstract

Dehydroepiandrosterone (DHEA) is an abundant steroid and precursor of sex hormones. During aging, the reduction in DHEA synthesis causes a significant depletion of estrogens and androgens in different organs, such as the ovaries, brain, and liver. Primary Biliary Cholangitis (PBC) is a cholestatic liver disease that begins with immune-mediated bile duct damage, and is followed by liver fibrosis, and finally, cirrhosis. PBC primarily affects postmenopausal women, with an average age of diagnosis of 65 years, but younger women are also affected. Here, we analyzed the levels of DHEA, estradiol (E2), and estriol (E3) in the PBC sera of females at an age of diagnosis under 40 (n = 37) and above 65 (n = 29). Our results indicate that in PBC patients at an age of diagnosis under 40, E2 was significantly lower compared to that in healthy women. In contrast, the levels of DHEA and E3 were in a normal range. Furthermore, ELISA assays revealed that in PBC patients at an age of diagnosis above 65, the levels of DHEA, E2, and E3 significantly declined in comparison to those in younger patients. In addition, flow cytometry analysis showed that the level of IL-8 significantly decreased while the level of TNF-α increased in older PBC patients compared to younger ones. Moreover, we showed for the first time that the sulfonated form of DHEA, DHEA-S, reduces the levels of both pro-inflammatory interleukins, IL-8 and TNF-α, in PBC-like cholangiocytes (H69-miR506), while it diminishes the level of the pro-fibrotic interleukin, IL-13, in hepatocytes (Hep-G2). Finally, we demonstrated that the expression of the pro-fibrotic agent TGF-β significantly increased in both the early (F0–F3) and cirrhotic (F4) stages of PBC, and this elevation was accompanied by higher α-SMA expression.

Metabolomics-based Investigation of Primary Biliary Cholangitis: A Cholestatic Liver Disease

“…The in ammatory response and brosis associated with PBC can potentially be modulated by DHEA (dehydroepiandrosterone) and its metabolites. Previous works have shown that the sulfonated metabolite, DHEA-S, can reduce the levels of pro-in ammatory interleukins (IL-8 and TNF-α) in PBC-like cholangiocytes, as well as the pro-brotic interleukin IL-13 in hepatocytes (Blatkiewicz et al in 2023). Furthermore, DHEA has also been shown to have a protective function in hepatocytes against oxidative stress induced by tert-butylhydroquinone (tBHQ), as well as apoptosis in HEPG2 cells (Kilanczyk et al in 2022).…”

Identification and Analysis of Sex-Biased MicroRNAs in Human Diseases

“…Kahnamoui et al found that respiratory sensitivity was associated with miRNA expression levels in mice of different sexes [ 8 ]; Rosenberg et al found an association between the effects of different sexes on smoking and lung development [ 9 ]. In addition, research showed that certain miRNAs are expressed differently in different sexes during fetal development [ 10 , 11 ], which, in turn, results in different developmental processes. There have even been studies of male–female gender differences in miRNA-associated methylation modifications during solid tumor pathology [ 12 ].…”