Department of Hepatobiliary Surgery and Visceral Transplantation, Clinic for Visceral, Transplant, Thoracic and Vascular Surgery, Leipzig University Medical Center, 04103, Leipzig, Germany.
Saxonian Incubator for Clinical Translation (SIKT), Leipzig University, 04103, Leipzig, Germany.
BMC Endocr Disord. 2024 Aug 1;24(1):135. doi: 10.1186/s12902-024-01663-9.
Prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is higher in men than in women. Hormonal and genetic causes may account for the sex differences in MASLD. Current human in vitro liver models do not sufficiently take the influence of biological sex and sex hormones into consideration.
Primary human hepatocytes (PHHs) were isolated from liver specimen of female and male donors and cultured with sex hormones (17β-estradiol, testosterone and progesterone) for up to 72 h. mRNA expression levels of 8 hepatic lipid metabolism genes were analyzed by RT-qPCR. Sex hormones and their metabolites were determined in cell culture supernatants by LC-MS analyses.
A sex-specific expression was observed for LDLR (low density lipoprotein receptor) with higher mRNA levels in male than female PHHs. All three sex hormones were metabolized by PHHs and the effects of hormones on gene expression levels varied depending on hepatocyte sex. Only in female PHHs, 17β-estradiol treatment affected expression levels of PPARA (peroxisome proliferator-activated receptor alpha), LIPC (hepatic lipase) and APOL2 (apolipoprotein L2). Further changes in mRNA levels of female PHHs were observed for ABCA1 (ATP-binding cassette, sub-family A, member 1) after testosterone and for ABCA1, APOA5 (apolipoprotein A-V) and PPARA after progesterone treatment. Only the male PHHs showed changing mRNA levels for LDLR after 17β-estradiol and for APOA5 after testosterone treatment.
Male and female PHHs showed differences in their expression levels of hepatic lipid metabolism genes and their responsiveness towards sex hormones. Thus, cellular sex should be considered, especially when investigating the pathophysiological mechanisms of MASLD.
代谢功能相关脂肪性肝病（MASLD）的患病率在男性中高于女性。激素和遗传原因可能导致 MASLD 的性别差异。目前的人类体外肝脏模型没有充分考虑到生物学性别和性激素的影响。
从女性和男性供体的肝标本中分离原代人肝细胞（PHH），并用人绒毛膜促性腺激素（17β-雌二醇、睾酮和孕酮）培养长达 72 小时。通过 RT-qPCR 分析 8 种肝脂质代谢基因的 mRNA 表达水平。通过 LC-MS 分析测定细胞培养上清液中的性激素及其代谢物。
观察到 LDLR（低密度脂蛋白受体）的性别特异性表达，男性 PHH 的 mRNA 水平高于女性 PHH。三种性激素均被 PHH 代谢，激素对基因表达水平的影响取决于肝细胞的性别。只有在女性 PHH 中，17β-雌二醇处理影响 PPARA（过氧化物酶体增殖物激活受体α）、LIPC（肝脂酶）和 APOL2（载脂蛋白 L2）的表达水平。进一步观察到，在女性 PHH 中，睾酮处理后 ABCA1（ATP 结合盒，亚家族 A，成员 1）的 mRNA 水平发生变化，孕激素处理后 ABCA1、APOA5（载脂蛋白 A-V）和 PPARA 的 mRNA 水平也发生变化。只有男性 PHH 在 17β-雌二醇处理后 LDLR 和睾酮处理后 APOA5 的 mRNA 水平发生变化。
男性和女性 PHH 在肝脂质代谢基因的表达水平及其对性激素的反应性方面存在差异。因此，尤其是在研究 MASLD 的病理生理机制时，应考虑细胞性别。
