Castanho Martins Maria, Dixon Emmanuel Dauda, Lupo Giulia, Claudel Thierry, Trauner Michael, Rombouts Krista
Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK.
Hans Popper Laboratory of Molecular Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
Liver Int. 2025 Apr;45(4):e16117. doi: 10.1111/liv.16117. Epub 2024 Oct 12.
Since its discovery, the patatin-like phospholipase domain containing 3 (PNPLA3) (rs738409 C>G p.I148M) variant has been studied extensively to unravel its molecular function. Although several studies proved a causal relationship between the PNPLA3 I148M variant and MASLD development and particularly fibrosis, the pathological mechanisms promoting this phenotype have not yet been fully clarified.
We summarise the latest data regarding the PNPLA3 I148M variant in hepatic stellate cells (HSCs) activation and macrophage biology or the path to inflammation-induced fibrosis.
Elegant but contradictory studies have ascribed PNPLA3 a hydrolase or an acyltransferase function. The PNPLA3 I148M results in hepatic lipid accumulation, which predisposes the hepatocyte to lipotoxicity and lipo-apoptosis, producing DAMPs, cytokines and chemokines leading to recruitment and activation of macrophages and HSCs, propagating fibrosis. Recent studies showed that the PNPLA3 I148M variant alters HSCs biology via attenuation of PPARγ, AP-1, LXRα and TGFβ activity and signalling.
The advent of refined techniques in isolating HSCs has made PNPLA3's direct role in HSCs for liver fibrosis development more apparent. However, many other mechanisms still need detailed investigations.
自发现以来，含patatin样磷脂酶结构域3（PNPLA3）（rs738409 C>G p.I148M）变体已被广泛研究，以阐明其分子功能。尽管多项研究证明PNPLA3 I148M变体与代谢相关脂肪性肝病（MASLD）的发展尤其是纤维化之间存在因果关系，但促进这种表型的病理机制尚未完全阐明。
我们总结了关于PNPLA3 I148M变体在肝星状细胞（HSC）激活和巨噬细胞生物学或炎症诱导纤维化途径方面的最新数据。
精妙但相互矛盾的研究赋予了PNPLA3水解酶或酰基转移酶功能。PNPLA3 I148M导致肝脏脂质蓄积，使肝细胞易发生脂毒性和脂凋亡，产生损伤相关分子模式（DAMP）、细胞因子和趋化因子，导致巨噬细胞和HSC募集和激活，进而促进纤维化。最近的研究表明，PNPLA3 I148M变体通过减弱过氧化物酶体增殖物激活受体γ（PPARγ）、活化蛋白-1（AP-1）、肝X受体α（LXRα）和转化生长因子β（TGFβ）的活性及信号传导来改变HSC生物学特性。
分离HSC的精细技术的出现，使PNPLA3在肝纤维化发展的HSC中的直接作用更加明显。然而，许多其他机制仍需要详细研究。
