Letter to the Editor: Prospects for applying the results of studying the Sonic Hedgehog pathway to the diagnosis of metabolic dysfunction-associated steatohepatitis

Abstract

Metabolic dysfunction-associated steatotic liver disease relates to the most common liver diseases, often leading to complications, and is one of the most relevant problems in clinical medicine. The Sonic Hedgehog (SHH) signaling pathway plays a key role in embryonic development in animals, controlling organogenesis, tissue homeostasis, and regeneration. In recent years, the role of SHH in the carcinogenesis and the development of metabolic dysfunction-associated steatohepatitis has been actively investigated. Several studies have demonstrated that SHH dysregulation is associated with progression of non-alcoholic steatohepatitis. In this regard, the work of Han et al in the World Journal of Gastroenterology, which, as a result of studying 190 metabolic dysfunction-associated steatohepatitis patients, established an association between the SHH protein content in the liver and the histological level of steatosis, hepatocyte ballooning, lobular inflammation and liver fibrosis stage, is undoubtedly very promising and creates real opportunities for the implementation of modern fundamental knowledge into clinical practice.

Key Words: Sonic Hedgehog; Hedgehog signaling; Metabolic dysfunction-associated steatohepatitis; Liver fibrosis; Hepatocyte ballooning

Core Tip: The Sonic Hedgehog (SHH) signaling plays an important role in the development of animals by regulating organogenesis, tissue homeostasis, and regeneration. In a number of studies, it has been established that SHH dysregulation is associated with progression of metabolic dysfunction-associated steatohepatitis. In this regard, Han et al, who combined modern fundamental ideas with a high-class histological examination of the liver and established a strong correlation of SHH with steatosis, inflammation and liver fibrosis in metabolic dysfunction-associated steatohepatitis patients, certainly deserve approval and further development of their research.

TO THE EDITOR

The high prevalence[1], changes in nomenclature[2], development of diagnostic and treatment principles, significant frequency of complications[3,4] make the problem of metabolic dysfunction-associated steatotic liver disease (MASLD) one of the most relevant in clinical medicine. However, current work shows that many aspects of MASLD diagnosis and treatment require further study[5,6].

The Sonic Hedgehog (SHH) signaling plays a critical role in embryonic development in animals, controlling organogenesis, tissue homeostasis, and regeneration[7]. SHH continues to function in the postnatal period, regulating the differentiation, proliferation and maintenance of body tissues, and also participating in the control of metabolic processes[8].

DISCOVERY HISTORY OF THE HEDGEHOG SIGNALING PATHWAY

The Hedgehog gene was first identified in the fruit fly Drosophila melanogaster by Nüsslein-Volhard and Wieschaus[9], whose results were published in 1980, and the authors received the Nobel Prize for their discovery in 1995. The Hedgehog gene controls the segmentation pattern of the Drosophila embryos and is named for the spiky, hedgehog-like phenotype that results from a loss-of-function mutation in embryos. Studies searching for a vertebrate equivalent of the Hedgehog gene have identified 3 homologous genes: Desert Hedgehog, Indian Hedgehog, and SHH, of which the SHH gene and the SHH protein are the best studied[10].

NORMAL FUNCTION OF THE SHH SIGNALING PATHWAY

In the adult human body, the SHH pathway is mostly inactive or weakly active, but it plays a crucial role in activating regenerative processes. The SHH signaling is involved in the protection of pluripotent cells and somatic stem cells, which are important for the recovery of neurons, chondrocytes, bone and muscle cells after damage[11,12]. In addition, recent studies have shown that the developmental morphogen HH and its downline signaling are involved in control of metabolism. Activation and regulation of the SHH signaling with downstream signaling pathways (Wnt/β-catenin, Notch, transforming growth factor-beta, mammalian target of rapamycin) is being studied in metabolic diseases[13].

SHH SIGNALING IN CARCINOGENESIS

The role of the SHH signaling in carcinogenesis has been well studied. Overexpression of SHH stimulates proliferation and modulates cell renewal processes, which leads to the progression of gastrointestinal, prostate, and blood cancers[14-17]. Continuous stimulation of stem cells increases the probability of tumor progression and recurrence after chemotherapy[18].

SHH SIGNALING IN METABOLIC DISEASES

The mechanism of interaction between SHH and lipids is quite complex[19,20]. The SHH protein contains lipid fragments that can be modified by fatty acids and cholesterol at the N and C ends, which is necessary for the maturation, secretion, and biological activity of SHH[21]. The lipid-modified SHH protein has a high affinity for the cell membrane and is localized in microdomains of lipid rafts. Fatty acid acylation directs SHH to the membrane of the secretory cell, while cholesterol anchors them to the rafts of both the secretory and receiving cells, thereby preventing inadequate secretion and increasing stability in the target cell[22]. Alteration of lipid metabolism leads to disruption of SHH signaling, causing adipocyte differentiation disorders, the development of diabetes, obesity, MASLD, and impaired SHH signaling can modulate lipid metabolism[13,23].

Considerable attention is being paid to the study of the role of SHH in the development of metabolic dysfunction-associated steatohepatitis (MASH). A number of studies have shown that ballooning and apoptotic hepatocytes produce and release SHH ligands[24-26]. Studies on cultured hepatocytes and experimental animals with liver injury have demonstrated that stimulation of SHH secretion is caused by oxidative and endoplasmic reticulum cellular stress[25]. Studies performed on Drosophila have found that adult organisms can reactivate the SHH signaling pathway to regenerate their tissues during injury[26,27]. In addition, SHH ligands released by hepatocytes activate hepatic stellate cells[28,29], which play a key role in the pathogenesis of liver fibrosis[30]. This mechanism is universal. SHH ligands function as profibrogenic factors in various liver diseases[31,32], including MASH[33] and viral hepatitis C[34,35].

The clinical aspects of studying MASH in the context of SHH function are very interesting. To continue the well-known PIVENS study, which aimed to investigate the effect of vitamin E on non-alcoholic steatohepatitis (NASH), the authors performed immunohistochemical determination of SHH in liver biopsies from 30 patients with NASH treated with vitamin E and 29 individuals treated with placebo. The amount of SHH in hepatocytes in the treatment group correlated with the level of aspartate aminotransferase in serum (P < 0.0001), hepatocyte ballooning (P = 0.004) and fibrosis stage (P = 0.02). The response to treatment was associated with a decrease in the amount of SHH in hepatocytes (P = 0.007)[36]. Several studies have demonstrated SHH activation in patients with MASH, which correlated with hepatocyte ballooning and hepatic stellate cells stimulation[24,37,38]. In a study by Estep et al[39] 69 patients with confirmed NASH biopsy were examined. Expression of SHH protein in the liver correlated with hepatocyte ballooning degeneration, the stage of steatosis and liver fibrosis determined by morphological methods, and circulating forms of the epithelial cell structural protein cytokeratin 18 (M30 and M65)[39]. In this regard, the work of Han et al[40], published online in the World Journal of Gastroenterology, in which 190 patients with MASH were examined with liver biopsy and determination of SHH expression by immunohistochemistry, is extremely important and promising. The authors showed that SHH protein content in the liver correlated with histological steatosis grade (r = 0.502, P < 0.001), ballooning hepatocytes (r = 0.496, P < 0.001), lobular inflammation (r = 0.450, P < 0.001), and fibrosis stage (r = 0.303, P = 0.006). This allowed Han et al[40] to conclude that it is possible to use the determination of SHH and cytokeratin 8/18 proteins in the liver for the diagnosis of MASH. These results show that SHH immunohistochemistry, possibly in combination with a digital pathology artificial intelligence platform, could serve as an addition to standard diagnostic methods or even as a surrogate endpoint in clinical trials[40]. Undoubtedly, the study by Han et al[40], based on a modern fundamental basis, creates excellent opportunities for the development of new technologies for the diagnosis and treatment of MASH.

CONCLUSION

Certainly since the initial description by Ludwig et al[41] in 1980, a new nosological form, NASH, achieved great dynamics in understanding this problem. The work of Han et al[40] is useful because it is an example of rigorous research that is necessary to transform fundamental biological principles into objective diagnostic tools that the field of MASH research needs. Maintaining a balance between new ideas and real objective diagnostic criteria is a rational condition for further progress in this area.