Sato Satoshi, Iino Chikara, Sasada Takafumi, Furusawa Keisuke, Yoshida Kenta, Sawada Kaori, Mikami Tatsuya, Fukuda Shinsaku, Nakaji Shigeyuki, Sakuraba Hirotake
Department of Gastroenterology, Hematology and Clinical Immunology, Hirosaki University Graduate School of Medicine.
Department of Preemptive Medicine, Hirosaki University Graduate School of Medicine.
Environ Health Prev Med. 2025;30:17. doi: 10.1265/ehpm.24-00365.
Many factors are associated with the development and progression of liver fat and fibrosis; however, genetics and the gut microbiota are representative factors. Moreover, recent studies have indicated a link between host genes and the gut microbiota. This study investigated the effect of patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 (C > G), which has been reported to be most involved in the onset and progression of fatty liver, on liver fat and fibrosis in a cohort study related to gut microbiota in a non-fatty liver population.
This cohort study included 214 participants from the health check-up project in 2018 and 2022 who had non-fatty liver with controlled attenuation parameter (CAP) values <248 dB/m by FibroScan and were non-drinkers. Changes in CAP values and liver stiffness measurement (LSM), liver-related items, and gut microbiota from 2018 to 2022 were investigated separately for PNPLA3 rs738409 CC, CG, and GG genotypes.
Baseline values showed no difference among the PNPLA3 rs738409 genotypes for any of the measurement items. From 2018 to 2022, the PNPLA3 rs738409 CG and GG genotype groups showed a significant increase in CAP and body mass index; no significant change was observed in the CC genotype group. LSM increased in all genotypes, but the rate of increase was highest in the GG genotype, followed by the CG and CC genotypes. Fasting blood glucose levels increased in all genotypes; however, HOMA-IR (Homeostasis Model Assessment of Insulin Resistance) increased significantly only in the GG genotype. HDL (high-density lipoprotein) and LDL (low-density lipoprotein) cholesterol levels significantly increased in all genotypes, whereas triglycerides did not show any significant changes in any genotype. As for the gut microbiota, the relative abundance of Feacalibacterium in the PNPLA3 rs738409 GG genotype decreased by 2% over 4 years, more than 2-fold compared to CC and GG genotypes. Blautia increased significantly in the CC group.
The results suggest that PNPLA3 G-allele carriers of non-fatty liver develop liver fat and fibrosis due to not only obesity and insulin resistance but also the deterioration of gut microbiota, which may require a relatively long course of time, even years.
许多因素与肝脏脂肪和纤维化的发生及进展相关；然而，遗传因素和肠道微生物群是典型因素。此外，近期研究表明宿主基因与肠道微生物群之间存在联系。本研究在一项针对非脂肪肝人群肠道微生物群的队列研究中，调查了据报道与脂肪肝发病和进展最为相关的含帕他丁样磷脂酶结构域蛋白3（PNPLA3）rs738409（C＞G）对肝脏脂肪和纤维化的影响。
这项队列研究纳入了2018年和2022年健康体检项目中的214名参与者，这些参与者患有非脂肪肝，通过FibroScan测得的受控衰减参数（CAP）值＜248dB/m，且不饮酒。分别针对PNPLA3 rs738409 CC、CG和GG基因型，调查了2018年至2022年期间CAP值和肝脏硬度测量值（LSM）、肝脏相关指标以及肠道微生物群的变化。
对于任何测量指标，PNPLA3 rs738409基因型的基线值均无差异。从2018年到2022年，PNPLA3 rs738409 CG和GG基因型组的CAP和体重指数显著增加；CC基因型组未观察到显著变化。所有基因型的LSM均升高，但GG基因型的升高速率最高，其次是CG和CC基因型。所有基因型的空腹血糖水平均升高；然而，稳态模型胰岛素抵抗评估（HOMA-IR）仅在GG基因型中显著升高。所有基因型的高密度脂蛋白（HDL）和低密度脂蛋白（LDL）胆固醇水平均显著升高，而甘油三酯在任何基因型中均未显示出任何显著变化。至于肠道微生物群，PNPLA3 rs738409 GG基因型中粪杆菌的相对丰度在4年内下降了2%，与CC和CG基因型相比下降幅度超过2倍。CC组中布劳特氏菌显著增加。
结果表明，非脂肪肝的PNPLA3 G等位基因携带者不仅由于肥胖和胰岛素抵抗，还由于肠道微生物群的恶化而发生肝脏脂肪和纤维化，这可能需要相对较长的时间进程，甚至数年。
