PNPLA3 is one of the bridges between TM6SF2 E167K variant and MASLD: Correspondence to editorial on “TM6SF2 E167K variant decreases PNPLA3-mediated PUFA transfer to promote hepatic steatosis and injury in MASLD”

Article information

Clin Mol Hepatol. 2025;31(1):e67-e69

Publication date (electronic) : 2024 September 10

doi : https://doi.org/10.3350/cmh.2024.0744

Baokai Sun¹, Likun Zhuang^,2

¹Department of Infectious Diseases, Qingdao Municipal Hospital, Qingdao University, Qingdao, China

²Central Laboratories, Qingdao Municipal Hospital, Qingdao University, Qingdao, China

Corresponding author : Likun Zhuang Central Laboratories, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, China Tel: +86-053288905295, Fax: +86-053288905295, E-mail: zlk0823@163.com

Editor: Han Ah Lee, Chung-Ang University College of Medicine, Korea

Received 2024 September 3; Accepted 2024 September 7.

Dear Editor,

We sincerely thank Drs. Andrea Caddeo and Rosellina M. Mancina for the thoughtful commentary on our recently published paper titled “TM6SF2 E167K variant decreases PNPLA3-mediated PUFA transfer to promote hepatic steatosis and injury in MASLD” [1,2]. The editorial provides a concise and comprehensive summary of our main findings and highlights the novelty of the mechanism by which the transmembrane 6 superfamily member 2 (TM6SF2) E167K variant increases the susceptibility of metabolic dysfunctionassociated steatotic liver disease (MASLD). In our study, the results revealed the TM6SF2 E167K variant-enhanced interaction between TM6SF2 and patatin-like phospholipase domain-containing protein 3 (PNPLA3) protein to inhibit the PNPLA3-mediated transfer of polyunsaturated fatty acids (PUFAs) from triglyceride (TG) to phosphatidylcholine (PC), as well as the potential value of dietary interventions with PC containing C18:3 for MASLD patients carrying the TM6SF2 E167K variant. The comments from the editorial underscore the strengths of our research and provide important suggestions for future research directions in this field.

The rising prevalence and burden of MASLD and its related complications highlight the importance of investigating the pathogenesis and identifying the potential therapeutic targets [3-5]. The TM6SF2 E167K variant is positively associated with the occurrence of MASLD and the variant could aggravate hepatic steatosis of male mice fed with high-fat diet (HFD) [6-8]. TM6SF2 is localized on the endoplasmic reticulum (ER) and is closely associated with the secretion of very-low-density lipoproteins (VLDL) in hepatocytes [6,9]. A prevailing view for the mechanism of TM6SF2 E167K variant-mediated MASLD occurrence is that E167K variant could reduce the stability and expression level of TM6SF2 protein, leading to the impaired secretion of TGriched VLDL from hepatocytes, which ultimately results in increased hepatic TG accumulation and decreased circulating TG level [6,10]. These findings suggest that the TM6SF2 E167K variant is likely a loss-of-function mutation. Studies also showed that TM6SF2 E167K variant carriers with MASLD had lower plasma TG level [6,7]. However, in the study by Luukkonen et al., there was no significant difference in total plasma TG level between TM6SF2 E167K variant carriers and non-carriers with MASLD.11 Additionally, Fan et al. [12] revealed an increase in plasma TG level in TM6SF2 knockout mice fed with HFD, and our study also did not observe a reduction in plasma TG level of HFD-fed mice with the TM6SF2 E167K variant. As suggested by the editorial, we would attempt to validate the conclusions drawn from the animal experiments using human liver organoids in the future study. The data from our and other groups suggest that the function of TM6SF2 E167K variant in MASLD occurrence might not be solely related to VLDL secretion, and a single theory based on loss of function is insufficient to fully explain the pathogenic mechanism of the TM6SF2 E167K variant in the development of MASLD.

PNPLA3 is considered to act as an acyltransferase that transfers PUFAs from TG to soluble phospholipids such as PC, or as a TG-hydrolyzing enzyme that hydrolyzes PUFAs from TG [13]. Our study revealed the interaction between TM6SF2 and PNPLA3 protein for the first time. We also identified that the TM6SF2 E167K variant could enhance the interaction between TM6SF2 and PNPLA3, leading to PNPLA3 accumulation in the ER to disrupt the PNPLA3-mediated transport of PUFAs from TG to PC, which ultimately resulted in increased hepatic polyunsaturated TG level and decreased polyunsaturated PC level. This remodeling of PUFAs in PC and TG was also associated with elevated levels of MDA and ROS, and reduced hepatocyte membrane fluidity. The study on human hepatic lipid metabolism showed a deficiency in hepatic polyunsaturated PC in TM6SF2 E167K variant carriers with MASLD,11 which is consistent with our hypothesis. Our finding provides new scientific evidence for elucidating the pathogenesis of MASLD, and represents a second pathway, in addition to impaired VLDL secretion, by which the TM6SF2 E167K variant increases the severity of MASLD.

As stated in the editorial, we do not exclude the possibility that the TM6SF2 E167K variant might also contribute to MASLD progression through other pathways. Genetic studies indicated that lower level of membrane bound O-acyltransferase domain containing 7 (MBOAT7) in human hepatocytes increased the severity of MASLD [14], and MBOAT7 was also involved in the acyl chain remodeling of phospholipids and TG [15]. It would be interesting to test whether the TM6SF2 E167K variant could promote MASLD progression by other established genetic risk factors, such as MBOAT7 or other molecules.

Here, we propose that the mechanisms by which the TM6SF2 E167K variant promotes MASLD progression might involve multiple pathways (Fig. 1). The TM6SF2 E167K variant not only impairs hepatic VLDL-TG secretion but also enhances its interaction with PNPLA3 in hepato-cytes to participate in the MASLD occurrence and progression. Additionally, other unidentified pathogenic mechanisms might also contribute to this process.

Figure 1.

Mechanisms for TM6SF2 E167K variant-mediated occurrence and progression of MASLD. MASLD, metabolic dysfunction- associated steatotic liver disease; PC, phosphatidylcholine; PNPLA3, patatin-like phospholipase domain-containing protein 3; PUFAs, polyunsaturated fatty acids; TG, triglyceride; TM6SF2, transmembrane 6 superfamily member 2; VLDL, very-low-density lipoprotein.