Correspondence to editorial on “GOLM1 promotes cholesterol gallstone formation via ABCG5-mediated cholesterol efflux in MASH livers”
Article information
Dear Editor,
We are grateful to Drs. Yoon-su Ha, Won Kim, and Seung-Jin Kim for their valuable feedback regarding our findings [1]. As one of the most prevalent chronic liver diseases, metabolic dysfunction-associated steatohepatitis (MASH) is associated with the onset of cholesterol gallstone (CGS) formation [2,3]. Golgi membrane protein 1 (GOLM1) increases ATP-binding cassette subfamily G member 5 (ABCG5)-mediated cholesterol efflux in an osteopontin (OPN)-dependent manner, promoting MASH-related CGS formation [2]. Moreover, interleukin-1β (IL-1β), a crucial inflammatory factor in MASH, increases GOLM1 expression and promotes its nuclear translocation [2]. As noted in the comments, multifaceted challenges remain, including sex-specific factors, the construction of gene-edited mice, and the application of disease models, which must be addressed to increase the translational potential of the research.
Sex is one of the most important factors affecting metabolic diseases, including MASH and gallstones [4,5]. Owing to the effects of hormones, particularly estrogen, females are more susceptible to cholesterol gallstones than males are [4,6]. Moreover, a recent study showed that estrogen protects against MASH [7]. The liver, a vital metabolic organ, is crucial for maintaining cholesterol homeostasis, with cholesterol being a key toxic molecule in MASH progression [8]. Estrogen potentially inhibits the progression of MASH by increasing hepatic exocytosis of cholesterol, which could lead to biliary cholesterol supersaturation and CGS formation. Cholesterol can be converted into steroid hormones such as estradiol [9]. Our previous study revealed that GOLM1 expression can be regulated by cholesterol [10]. Therefore, sex-related factors such as estrogen may contribute to the formation of MASH-associated CGSs by regulating GOLM1 expression. Our study focused on the role of GOLM1 in MASH-related CGS formation [2]. To ensure the reliability of the study, we controlled for sex as a confounder to exclude potential interference. Although this design avoided interference from the above factors in the study results, it prevented us from assessing the effects of sex-related factors, especially estrogen, on MASH-related gallstone formation. Further clinical and fundamental research is needed to clarify the impact of sex on MASH-related CGSs.
Global knockout is a well-established gene editing technique that accurately reflects gene function and prevents residual expression of the knocked out gene. However, global knockouts may induce compensatory effects and lack spatial and temporal specificity. GOLM1 is a Golgi type II transmembrane protein that is found mainly in the liver and that participates in protein transport and modification [2]. It is normally expressed at low levels in hepatocytes but is highly expressed in MASH livers [2]. Moreover, high GOLM1 expression is associated with pathological features of MASH, such as liver inflammation and fibrosis, suggesting that GOLM1 plays a specific role in MASH [2]. Considering the liver specificity of GOLM1 expression, global gene knockout could fulfill these research needs to some extent. Tissue-specific knockout mice will help explore the role of GOLM1 in specific tissues in MASH-related CGS formation while minimizing compensatory effects from other tissues. Although GOLM1 is specifically expressed in the liver, secreted GOLM1 may originate from other tissues, so efforts should focus on excluding its influence. Adipose tissue is one of the major components of the human body and plays an important role in regulating metabolism and inflammation [11]. In addition to regulating cholesterol metabolism, GOLM1 is involved in the inflammatory response [12]. Hence, adipose tissue may regulate GOLM expression, thus impacting MASH-associated CGS formation. The presence of GOLM1 in adipose tissue and the role of adipose tissue-derived GOLM1 in MASH-related CGSs are promising directions and need to be further explored.
A high-fat, high-carbohydrate diet predominates in Western society, and feeding animals this type of diet is the traditional approach used to construct animal models of metabolic dysfunction-associated fatty liver disease (MAFLD) and MASH [1,13,14]. Our study demonstrated that all the mice fed a high-fat diet (HFD) developed MASH, which was accompanied by liver inflammation and ballooning [2]. However, as noted in the comments, MASH is a complex liver disease, and findings are best validated using multiple models. Common dietary methods for modeling MASH include fatty acid diets, choline-deficient L-amino-defined diets (CDAA), methionine choline-deficient diets (MCD), and high-fat, high-cholesterol diets (HFHC) [13]. These diets can be used to establish both acute and chronic MASH models, providing more comprehensive data to support research. Importantly, animal models cannot fully replicate human MASH, and additional clinical data are required to bridge this gap [15].
Notes
Authors’ contribution
Yi-Tong Li, Wei-Qing Shao, and Zhen-Mei Chen designed and wrote the manuscript; Jin-Hong Chen and Jing Lin supervised the manuscript.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (Grant No. 82272836, 82470667) and Shanghai Excellent Academic Leaders Program (Grant No. 22XD1400300).
Conflicts of Interest
The authors declare no competing interests.
Abbreviations
ABCG5/8
ATP-binding cassette subfamily G member 5/8
CDAA
choline-deficient L-amino-defined diets
CGS
cholesterol gallstone
GOLM1
golgi membrane protein 1
HFD
high-fat diet
HFHC
high-fat
IL-1β
interleukin-1β
MAFLD
metabolic dysfunction-associated fatty liver disease
MASH
metabolic dysfunction-associated steatohepatitis
MCD
methionine choline-deficient diets
OPN
osteopontin