Liver

Overview of Liver Diseases

Liver diseases are complex disorders that include viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease, liver cirrhosis, liver failure, and liver cancers. Chronic liver diseases account for two million deaths globally and are the 11th highest cause of death. These diseases are also associated with a bleak long-term prognosis. Hence, there is a pressing need for more effective treatments to tackle this public health issue (1).

Liver diseases often happen due to cellular oxidative stress and inflammation, leading to excessive producing of extracellular matrix by hepatic stellate cells (2). These events cause changes in the liver’s structure and lead to issues such as dysfunction, fibrosis, cirrhosis, and even hepatocellular carcinoma. Symptoms vary and may include stomach and leg swelling, bruising easily, changes in stool and urine color, and jaundice or yellowing of the skin and eyes (3).

Metabolic disorders such as obesity, hyperlipidemia, and diabetes; alcohol use disorder; high fat intake; viral hepatitis infections; long-term use of some hepatotoxic drugs, such as anti-tuberculous drugs, acetaminophen, and protease inhibitors; genetic disorders such as Alpha-1 antitrypsin deficiency and Wilson disease; and malnutrition are some of the risk factors linked with chronic liver disease (4, 5, 6).

Liver diseases occur gradually and may be challenging to treat when it manifests irreversible changes (2). Drug therapy is the primary approach to treating the disease. Surgery may be recommended for early-stage hepatocellular carcinoma. However, it shows poor efficacy and a high recurrence rate. Liver transplantation is the only effective treatment for end-stage liver diseases. Still, it is limited due to the unavailability of livers to meet the growing number of patients and the adverse effects of lifelong medication.

Liver dysfunction and its associated pathways

Hepatic Cholestasis

Hepatic cholestasis is characterized by reduced or stalled bile secretion and flow, resulting in accumulated bile constituents in the blood, including bilirubin and bile acids. It can happen due to an impairment in the ability of hepatocytes to produce bile or a blockage disrupting bile release (7).

Cholestasis may occur with mutations in genes involved in bile secretion, a condition called familial intrahepatic cholestasis. Genes involved with familial intrahepatic cholestasis include ATP8B1, ABCB1, TJP2, NR1H4, and MYO5B (8).

Hepatic Fibrosis and Hepatic Stellate Cell Activation

Hepatic fibrosis is a chronic liver disease that occurs when there is a build-up of extracellular matrix in the liver (8). Hepatic stellate cell (HSC) activation, inflammation, and cellular stress responses due to chronic liver injury contribute to this condition (9).

In particular, activated HSCs are the principal drivers of hepatic fibrosis. Exploring the pathways involved in HSC activation, including Notch, Wnt/β-catenin, Hedgehog, TGFβ/Smad, and Hippo, can lead to a deeper understanding of this condition and developing more effective therapies (10).

Other signaling pathways involved in liver diseases

Many liver diseases are preventable and treatable with early diagnosis (1). Left undiagnosed and untreated, liver diseases can progress to advanced stages, leading to liver failure and associated complications like hepatic encephalopathy and coagulopathy. A deeper understanding of the mechanisms involved in liver disease, including the related signaling pathways, can provide valuable insights into the disease's pathogenesis and progression. It may also guide researchers toward developing more effective treatments targeting these pathways.

Adiponectin signaling

Adiponectin is a hormone secreted by the adipose tissue, bone, placenta, cardiac muscle cells, pituitary gland, and skeletal muscle (11). It modulates glucose and lipid metabolism and supports insulin sensitivity. It is inversely associated with lipid accumulation, inflammation, and liver diseases such as non-alcoholic fatty liver disease.  Adiponectin signaling is activated by the binding of adiponectin with its specific receptors, AdipoR1 and AdipoR2.

Research suggests that adiponectin may protect against liver injury. The onset of liver disease, such as non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, liver fibrosis, and liver cancer, is associated with a decrease in adiponectin, reduced adiponectin receptor expression, and aberrant adiponectin signaling. Conversely, increased adiponectin levels lead to a significant improvement in these liver pathologies (11).

Hence, it has been recommended that researchers focus on developing treatments that increase the levels of adiponectin and its receptor. So far, evidence suggests that dietary polyphenols, which may increase adiponectin levels, may protect against non-alcoholic fatty liver disease and other metabolic pathologies, including insulin resistance. Further research is needed to determine whether administering adiponectin can be beneficial in preventing and managing liver diseases (12).

Notch signaling

The Notch pathway comprises Notch receptors (Notch1-4), Delta-like ligands (Dll)-1,-3, and -4, and Serrate-like ligands (Jagged-1 and -2) and is activated through the binding of Notch ligands and receptors between neighboring cells (13).

Notch signaling works to regulate organ development, repair, and regeneration. Its dysregulation is associated with several liver pathologies. For instance, Notch signaling is involved in bile duct development, morphogenesis, and maintenance. Bile duct morphogenesis can be impaired when Notch signaling is lost or reduced in hepatoblasts, the hepatic progenitor cells, resulting in diseases like paucity of intrahepatic bile ducts (13).

More, about 95% of patients with Alagille syndrome (ALGS), a multisystem developmental disorder affecting the bile duct, heart, kidney, skeleton, and other organs, have been shown to have a mutation in JAG1 and around 2% in NOTCH2. The increased expression of Notch-3 and JAG1 characterizes liver fibrosis (14). Aberrant Notch signaling has also been identified in liver cancers (15). It may contribute to cancer formation by activating Sox9 and K19, transcription factors identified as hepatocellular carcinoma markers. Selective Notch1 inhibition has been shown to prevent cancer cell growth and limit angiogenesis (16, 17, 18).

Studies on the relevance of Notch signaling in liver development and disease have grown in recent years due to its wide-ranging significance and regulatory role (13). However, more research is needed to understand its therapeutic benefits in treating patients with liver diseases (15).  

Hedgehog signaling

Hedgehog signaling has four main components: the ligand Hedgehog, receptor Patched, signal transducer Smoothened, and effector transcription factor Gli. It is crucial for liver development, repair, and regeneration (19).

Hedgehog signaling is mostly inactive in the healthy adult liver but becomes reactivated in response to liver injury to support repair (20). The pathway must return to dormant after liver repair to ensure proper recovery; otherwise, tissue damage may ensue.

Aberrant activation of Hedgehog signaling is linked with the development and progression of liver diseases, including chronic viral hepatitis, hepatocellular carcinoma, cholangiocarcinoma, and alcoholic or nonalcoholic fatty liver disease. For instance, evidence suggests that the hedgehog signaling pathway is hyperactive, and the Hhip pathway inhibitor is less active in hepatocellular carcinoma (19). This increased pathway activity is linked to more significant tumor burden, invasion, metastasis, chemoresistance, and a poorer prognosis, such as a lower survival rate and an increased likelihood of recurrence after liver transplant.

Patients with primary biliary cholangitis and primary sclerosing cholangitis have been found to show elevated hedgehog pathway activity, and the level of Hedgehog activation is also strongly associated with the severity of liver fibrosis in these diseases (19). Additionally, research has demonstrated that Hedgehog activity in patients with alcoholic or nonalcoholic fatty liver disease is correlated with the degree of hepatic inflammation, liver cell injury or death, liver fibrosis, and the likelihood of liver-related complications and death.

Hedgehog inhibitors, such as Sonidegib, Capsaicin, and Forskolin, are being studied for treating various liver diseases. More studies will be vital for developing safe hedgehog-targeted therapies that promote liver regeneration while preventing liver-related complications (20).

WNT signaling

The Wnt pathway involves 19 Wnt genes, which are extracellularly secreted glycoproteins and ten receptors. It can function via the canonical pathway, which necessitates the B-catenin intracellular signal transducer, or a non-canonical pathway that does not require B-catenin. 

Wnt/β-catenin signaling is necessary for liver development, repair, regeneration, homeostasis, and other processes essential to liver function. Dysregulation of this pathway is strongly associated with the development and progression of many liver diseases, such as nonalcoholic fatty liver disease and liver cancers.

Wnt/β-catenin signaling is dormant in adults with healthy livers but can reactivate during regeneration, as it is a master regulator of liver regeneration. It can also become active in pathological circumstances (21). For instance, it’s been shown that Wnt/β-catenin signaling is hyperactivated and contributes to tumor growth and spread in liver cancers, including hepatocellular carcinoma, cholangiocarcinoma, and hepatoblastoma. Dysregulation of crucial modulators of Wnt/β-catenin signaling, including LRP6, Wnt1, Wnt3a, β-catenin, GSK-3β, and APC, has been found in cases of non-alcoholic fatty liver disease (22).

Inhibiting or downregulating Wnt/β-catenin signaling has been observed to slow down the pathological events associated with liver fibrosis, such as hepatic stellate cell activation and growth, collagen synthesis, inflammation, and angiogenesis (23).   Hence, the Wnt/β-catenin signaling pathway is a promising target for treating liver diseases, and further research on this pathway can lead to better clinical outcomes.

References

1. Yang, Yaqian, et al. Exploring the Potential of Treating Chronic Liver Disease Targeting the PI3K/Akt Pathway and Polarization Mechanism of Macrophages. Heliyon, vol. 9, no. 6, 2023, p. e17116.
2. Chen, Bangjie et al. cGAS-STING Signaling Pathway and Liver Disease: From Basic Research to Clinical Practice. Frontiers in pharmacology vol. 12 719644. 18 Aug. 2021.
3. National Library of Medicine https://medlineplus.gov/liverdiseases.html  (Accessed March 12, 2024)
4. Sharma A, Nagalli S. Chronic Liver Disease. [Updated 2023 Jul 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan.
5. Majid, Bushra, et al. Assessment of Knowledge About the Risk Factors of Chronic Liver Disease in Patients Admitted in Civil Hospital Karachi. Cureus, vol. 11, no. 10, 2019.
6. Banait, Shashank, et al. Risk Factors for Chronic Liver Disease in Population of Central India: A Case-control Study from Rural India. Egyptian Liver Journal, vol. 11, no. 1, 2021, pp. 1-9.
7. Shah R, John S. Cholestatic Jaundice. [Updated 2023 Jul 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan.
8. Li, Qinghong, and Yue Sun. A Link between Intrahepatic Cholestasis and Genetic Variations in Intracellular Trafficking Regulators. Biology, vol. 10, no. 2, 2021,
9. Baghaei, Kaveh, et al. Therapeutic Potential of Targeting Regulatory Mechanisms of Hepatic Stellate Cell Activation in Liver Fibrosis. Drug Discovery Today, vol. 27, no. 4, 2022, pp. 1044-1061
10. Yan, Yufei, et al. Extra- and Intra-Cellular Mechanisms of Hepatic Stellate Cell Activation. Biomedicines, vol. 9, no. 8, 2021.
11. Gamberi, Tania, et al. Adiponectin Signaling Pathways in Liver Diseases. Biomedicines, vol. 6, no. 2, 2018.
12. Shabalala, Samukelisiwe C., et al. The Effect of Adiponectin in the Pathogenesis of Non-alcoholic Fatty Liver Disease (NAFLD) and the Potential Role of Polyphenols in the Modulation of Adiponectin Signaling. Biomedicine & Pharmacotherapy, vol. 131, 2020, p. 110785.
13. Adams, Joshua M., and Hamed Jafar-Nejad. The Roles of Notch Signaling in Liver Development and Disease. Biomolecules, vol. 9, no. 10, 2019.
14. Bansal, Ruchi, et al. The Interplay of the Notch Signaling in Hepatic Stellate Cells and Macrophages Determines the Fate of Liver Fibrogenesis. Scientific Reports, vol. 5, no. 1, 2015, pp. 1-12.
15. Geisler, Fabian, and Mario Strazzabosco. Emerging Roles of Notch Signaling in Liver Disease. Hepatology (Baltimore, Md.), vol. 61, no. 1, 2014, p. 382.
16. Richtig, Georg et al. SOX9 is a proliferation and stem cell factor in hepatocellular carcinoma and possess widespread prognostic significance in different cancer types. PloS one vol. 12,11 e0187814. 9 Nov. 2017.
17. Kawai, Takayuki et al. Keratin 19, a Cancer Stem Cell Marker in Human Hepatocellular Carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research vol. 21,13 (2015): 3081-91.
18. Xu, Hao, and Lin Wang. The Role of Notch Signaling Pathway in Non-Alcoholic Fatty Liver Disease. Frontiers in Molecular Biosciences, vol. 8, 2021, p. 792667.
19. Machado, M. V., & Diehl, A. M. (2018). Hedgehog signalling in liver pathophysiology. Journal of hepatology, 68(3), 550–562.
20. Omenetti, Alessia, et al. Hedgehog Signaling in the Liver. Journal of Hepatology, vol. 54, no. 2, 2011, pp. 366-373.
21. Hu, Shikai, and Satdarshan P. Monga. Wnt/β-Catenin Signaling and Liver Regeneration: Circuit, Biology, and Opportunities. Gene Expression, vol. 20, no. 3, 2021, pp. 189-199.
22. Shree Harini, Karthik, and Devaraj Ezhilarasan. Wnt/Beta‐Catenin Signaling and Its Modulators in Nonalcoholic Fatty Liver Diseases. Hepatobiliary & Pancreatic Diseases International, vol. 22, no. 4, 2023, pp. 333-345
23. Duspara, Kristina et al. Targeting the Wnt Signaling Pathway in Liver Fibrosis for Drug Options: An Update. Journal of clinical and translational hepatology vol. 9,6 (2021): 960-971.