Matrix Gla Protein, a New Target Fighting Against Fibrosis of Nonalcoholic Steatohepatitis?

Nonalcoholic fatty liver disease (NAFLD, now also called metabolic dysfunction-associated steatotic liver disease [MASLD]) is a chronic liver disease linked to obesity and type 2 diabetes, affecting 30% of the global population.¹ Nonalcoholic steatohepatitis (NASH), its severe form, can lead to cirrhosis or hepatocellular carcinoma.² One strategy to reduce liver-related mortality is to prevent the progression of fibrogenesis, because hepatic fibrosis severity is one of the strongest prognostic indicators in chronic liver diseases, particularly NASH.³ Liver fibrosis is a complex process involving progressive accumulation of extracellular matrix (ECM) components, alterations in ECM degradation, and distortion of liver parenchyma in response to chronic damage. Fibrogenesis is driven primarily by the activation of hepatic stellate cells (HSCs), causing increased deposition of fibrillar ECM that negatively affects regeneration of the liver parenchyma over time.⁴ Subsequently, identifying new targets to halt or reverse liver fibrogenesis holds promise as a possible treatment for NASH.

The course of NAFLD varies owing to genetics, environmental factors, and divergent disease drivers. This variability makes it difficult to find effective drugs for all patients with NASH. The drug discovery process generally begins with treating cells in vitro, then moving to in vivo animal models, usually mice, before finally progressing to human clinical trials. A mouse NAFLD/NASH model would be useful if it can mimic the pathogenesis of human NAFLD/NASH. Mouse models are amenable to genetic dissection of complex traits, which helps identify potential genes and pathways for intervention in human beings. However, similar to the heterogeneity of human NAFLD/NASH, pathogenesis of NAFLD also varies significantly in different strains of mice in response to diet.⁵ In this issue of Cellular and Molecular Gastroenterology and Hepatology, Hui et al⁶ used an elegant hybrid mouse diversity panel that contains more than 100 inbred strains of mice. They used a "systems genetics" approach that integrated clinical and molecular traits with genetic mapping, correlating, and statistical modeling to identify matrix Gla protein (MGP) as a new target for NASH-associated fibrosis.

MGP is a small secretory vitamin K–dependent protein highly expressed by vascular smooth muscle cells and chondrocytes. MGP activates bone morphogenic protein 2 and bone morphogenic protein 4, and acts as a calcification inhibitor in cartilage and vasculature. Homozygous MGP-knockout mice die at approximately 2 months old owing to aberrant cartilage and arterial calcification.⁷ Using the global transcriptomic profiling of livers from the hybrid mouse diversity panel, Hui et al⁶ found that hepatic expression of Mgp was associated with liver fibrosis in both male and female mice. The expression of Mgp increased with time and correlated with the severity of NASH in mice and NASH patients. Single-cell RNA sequencing analysis revealed that Mgp was highly expressed in HSCs and dendritic cells, and Mergeomics analysis showed that Mgp expression was associated with several connective tissues, ECM genes, and regulators of fibrosis. Intriguingly, female but not male Mgp+/- mice had significantly decreased fibrosis induced by a NASH diet. Mechanistically, loss of MGP in cultured HSCs led to decreased response to transforming growth factor β owing to increased expression of the inhibitor SMAD6 (Suppressor of Mothers against Decapentaplegic 6), but decreased expression of regulator SMAD and transforming growth factor β–receptor expression. Together, this study identified MGP as a novel player in HSC activation and liver fibrosis in NASH progression.

Although this study identified MGP as a potential target for liver fibrosis during NASH progression, it has brought up several unanswered questions. One intriguing question is the role of sexual dimorphism in MGP and liver fibrosis. Loss of MGP attenuates fibrosis only in female mice, despite the hepatic expression of Mgp being the same in both genders. Sex hormones do not affect the expression of Mgp in mouse livers, so other risk factors for NASH and liver fibrosis such as intestinal permeability, microbiota, and changes in adipocyte tissues should be investigated in the future. Although the prevalence and severity of NAFLD are higher in men than in women, after menopause, NAFLD occurs at a higher rate in women, suggesting that estrogen is protective in human beings.⁸ Further research is required to determine the difference in hepatic expression of MGP between men and women, and whether estrogen has any effect on expression. Although HSCs are the primary source of myofibroblasts that contribute to liver fibrosis, other cell types, such as macrophages and liver sinusoidal endothelial cells, also are important microenvironment components that may contribute to HSC activation and fibrosis. Conducting cell type–specific ablation of MGP in mice could help to further examine its role in the pathogenesis of liver fibrosis. Lastly, there is a need to develop small pharmacologic MGP inhibitors to test the translational value of targeting MGP to fight against liver fibrosis and NASH progression.