Sex-dependent dynamics of metabolism in primary mouse hepatocytes

Abstract

The liver is one of the most sexually dimorphic organs. The hepatic metabolic pathways that are subject to sexual dimorphism include xenobiotic, amino acid and lipid metabolism. Non-alcoholic fatty liver disease and hepatocellular carcinoma are among diseases with sex-dependent prevalence, progression and outcome. Although male and female livers differ in their abilities to metabolize foreign compounds, including drugs, sex-dependent treatment and pharmacological dynamics are rarely applied in all relevant cases. Therefore, it is important to consider hepatic sexual dimorphism when developing new treatment strategies and to understand the underlying mechanisms in model systems. We isolated primary hepatocytes from male and female C57BL6/N mice and examined the sex-dependent transcriptome, proteome and extracellular metabolome parameters in the course of culturing them for 96 h. The sex-specific gene expression of the general xenobiotic pathway altered and the female-specific expression of Cyp2b13 and Cyp2b9 was significantly reduced during culture. Sex-dependent differences of several signaling pathways increased, including genes related to serotonin and melatonin degradation. Furthermore, the ratios of male and female gene expression were inversed for other pathways, such as amino acid degradation, beta-oxidation, androgen signaling and hepatic steatosis. Because the primary hepatocytes were cultivated without the influence of known regulators of sexual dimorphism, these results suggest currently unknown modulatory mechanisms of sexual dimorphism in vitro. The large sex-dependent differences in the regulation and dynamics of drug metabolism observed during cultivation can have an immense influence on the evaluation of pharmacodynamic processes when conducting initial preclinical trials to investigate potential new drugs.

A Panoramic View of Cell Population Dynamics in Mammalian Aging

“…Taking the liver as an example, we observed distinct separations in specific cell populations between females and males in hepatocytes ( fig. S8A-B ), consistent with previous research characterizing the liver as a “sexually dimorphic organ”( 35 , 36 ). This distinction is in line with known sex-specific variations in metabolic functions, such as superior alcohol clearance and lipid metabolism capabilities in males and heightened cholesterol metabolism abilities in females( 36 ).…”

“…S8A-B), consistent with previous research characterizing the liver as a "sexually dimorphic organ" (35,36). This distinction is in line with known sex-specific variations in metabolic functions, such as superior alcohol clearance and lipid metabolism capabilities in males and heightened cholesterol metabolism abilities in females (36). These sex-specific effects extend down to the sub-cluster level, as demonstrated by the identification of 73 sub-clusters displaying significant differential abundance between males and females across all age groups (fig.…”

Phospholipid isotope tracing reveals β-catenin-driven suppression of phosphatidylcholine metabolism in hepatocellular carcinoma

“…In humans, it has been reported that PEMT activity is increased by estrogen, and therefore females may be resistant to choline deprivation (Leermakers et al, 2015). Sex-specific differences have been well characterized in both HCC (Natri et al, 2019; Takemoto et al, 2005) and MASLD, MASH, and HCC risk (Lonardo et al, 2019), as well as in mouse primary hepatocytes (Hochmuth et al, 2021), obese mice (Savva et al, 2022), rats (Lomas-Soria et al, 2018), and the zebrafish liver transcriptome (Zheng et al, 2013). At least some of the increased susceptibility to hepatocarcinogenesis in males is due to the effects of estrogen, which inhibits pro-tumorigenic IL-6 production (Naugler et al, 2007).…”

Cytoskeleton alterations in non-alcoholic fatty liver disease

“…In these mice, fatty acid metabolism and pro-inflammatory genes were up-regulated 53 . Moreover, sexual dimorphic genes, such as Cyp1a2 and Esr1 (coding for a cytochrome P450 family member and an estrogen receptor, respectively) were de-regulated in mouse hepatocytes 54 . The liver is a sexually dimorphic organ 55 .…”