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. 2025:30:17.
doi: 10.1265/ehpm.24-00365.

A 4-year cohort study of the effects of PNPLA3 rs738409 genotypes on liver fat and fibrosis and gut microbiota in a non-fatty liver population

Satoshi Sato  1 , Chikara Iino  1 , Takafumi Sasada  1 , Keisuke Furusawa  1 , Kenta Yoshida  1 , Kaori Sawada  2 , Tatsuya Mikami  2 , Shinsaku Fukuda  2 , Shigeyuki Nakaji  2 , Hirotake Sakuraba  1
Affiliations

A 4-year cohort study of the effects of PNPLA3 rs738409 genotypes on liver fat and fibrosis and gut microbiota in a non-fatty liver population

Satoshi Sato et al. Environ Health Prev Med. 2025.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Cohort study; Gut microbiota; Liver fat; Liver fibrosis; Patatin-like phospholipase domain-containing 3 (PNPLA3).

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Conflict of interest statement

All authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Study enrollment flowchart.
Fig. 2
Fig. 2
Comparison of the diversity of gut microbiota in the PNPLA3 rs738409 SNP groups.
Fig. 3
Fig. 3
The LEfSe results of the gut microbiota between 2018 and 2022 by PNPLA3 SNPs.
Fig. 4
Fig. 4
Change in gut microbiota relative abundance from 2018 to 2022.
Fig. 5
Fig. 5
Comparison of changes in gut microbiota relative abundance from 2018 to 2022 by PNPLA3 genotype.
See this image and copyright information in PMC

References

    1. Castillo-Núñez Y, Almeda-Valdes P, González-Gálvez G, Arechavaleta-Granell MDR. Metabolic dysfunction-associated steatotic liver disease and atherosclerosis. Curr Diab Rep. 2024;24:158–66. https://link.springer.com/article/10.1007/s11892-024-01542-6. - DOI - PubMed
    1. Younossi ZM, Gramlich T, Matteoni CA, Boparai N, McCullough AJ. Nonalcoholic fatty liver disease in patients with type 2 diabetes. Clin Gastroenterol Hepatol. 2004;2:262–5. https://www.sciencedirect.com/science/article/pii/S154235650400014X?via%.... - PubMed
    1. Leite NC, Villela-Nogueira CA, Cardoso CR, Salles GF. Non-alcoholic fatty liver disease and diabetes: from physiopathological interplay to diagnosis and treatment. World J Gastroenterol. 2014;20:8377–92. https://www.wjgnet.com/1007-9327/full/v20/i26/8377.htm. - PMC - PubMed
    1. Rinella ME, Lazarus JV, Ratziu V, Francque SM, Sanyal AJ, Kanwal F, et al.. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. Hepatology. 2023;78:1966–86. https://journals.lww.com/hep/fulltext/2023/12000/a_multisociety_delphi_c.... - PMC - PubMed
    1. Riazi K, Azhari H, Charette JH, Underwood FE, King JA, Afshar EE, et al.. The prevalence and incidence of NAFLD worldwide: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2022;7:851–61. https://www.sciencedirect.com/science/article/abs/pii/S2468125322001650?.... - PubMed