Study Author Suggests Gender-Specific Treatments for NAFLD

The prevalence of nonalcoholic fatty liver disease (NAFLD) is significantly higher in men (33%) than women (20%), according to a Hepatology article.

The higher rate of NAFLD in men is confirmed by Youngmi Jung, professor at Pusan National University in Korea and colleagues writing in a Nature Communications article, but they set out to discover the reasons behind the disparity.

“Collectively, current evidence suggests that estrogen protects from NAFLD,” Jung wrote.

Notably, postmenopausal women on hormone replacement therapy (HRT) had a lower prevalence of NAFLD compared to postmenopausal women not on HRT, she noted. In a randomized clinical trial, combined HRT significantly decreased aminotransferase levels in postmenopausal women with type 2 diabetes and presumed NAFLD compared to placebo controls.

In addition, protein formyl peptide receptor 2 (FPR2) is known to play an important role in mediating inflammatory responses in multiple organs.

“However, no study so far has determined its role in the liver. Could FPR2 be involved in the sex-related differences regarding NAFLD prevalence and severity?,” Pusan National University said in a news release.

To answer the question, Jung and colleagues conducted a mice model study, and first found that FPR2 was highly expressed in healthy livers of female mice.

They found that FPR2 was expressed differently in the livers of male and female mice that were fed a special NAFLD-inducing diet. And silencing the FPR2 gene made the male and female mice equally vulnerable to NAFLD, suggesting that FPR2 has a protective effect on the liver.

The researchers also found that FPR2 production in the liver is mediated by estrogen. Males supplemented with external estrogen produced more FPR2 and were more resistant to NAFLD, whereas females that had their ovaries removed exhibited reduced liver FPR2 levels.

“Taken together, our findings suggest that FPR2 is a potential therapeutic target for developing pharmacological agents to treat NAFLD/NASH,” Jung said. “In addition, our results could help in the development of gender-based therapies for NASH.”

In general, the study of sex differences is a rapidly growing area of medicine, according to Jung.

“Physiological levels of sex hormones vary significantly throughout the reproductive and menstrual cycle in premenopausal women and influence physiological functions and disease susceptibility,” Jung wrote. “Thus, without considering sex and age, clinical and animal studies may fail to identify the influence of biological sex on study outcomes or arrive at erroneous conclusions.”

As a result, there is a “pressing need” for designing and developing better sex-balanced animal experiments, “considering that the sex-specific expression of FPR2 in the liver had been completely overlooked in previous studies,” Jung said.