by Shambhavi Mishra
T.Y.B.Sc Department of Biotechnology DES Fergusson College, Pune. For BTH3507
Blog Category: Organ Health and Medicine
Coffee is one of the most popular beverages across the world. According to latest statistics of International coffee organization, 1.4 billion cups of coffee is consumed everyday across the world. Despite this coffee has always been surrounded by controversies regarding its health benefits because of its caffeine content. But recently coffee has attracted scientists across the world as it has been claimed to have hepatoprotective characteristics.
Several researchers have carried out studies and the concluded that there exists an inverse relationship between amount of coffee consumption and vulnerability to liver fibrosis.
It has been observed that coffee consumption is correlated to reduced levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transferase (GGT) and alkaline phosphatase (ALP).
Let us start by understanding the basic cause and pathophysiology of liver fibrosis.
WHAT IS LIVER FIBROSIS- Liver fibrosis is formation of large number of scars in liver tissues, this happens when hepatocytes are trying to repair or replace dead and damaged cells.
Fibrosis starts to develop when it is repeatedly damaged by some hepatotoxicants like alcohol, viral hepatitis, auto immune hepatitis and many more.
So, the progression or pathophysiology of the disease is as follows-
· Figure 1 represents a normal liver which has hepatocytes and hepatic sinusoid lined by sinusoidal cells.
· Here we also have our stellate cells and Kupffer cell usually these stellate cells are at rest and are dormant but in fibrosis they are activated and Kupffer cells are macrophages of the liver.
Figure-1- Cross-section of a healthy liver tissue
Figure 2 shows liver with damaged hepatocytes
These damaged hepatocytes release Damage Associated Molecular Patterns (DAMPS) and reactive oxygen species.
These DAMPS now stimulate the Kupffer cells and stellate cells. Activated stellate cells secrete chemokines like CCL2 and stimulate macrophages and Kupffer cells to secret cytokines.
CCL2 will attract more immune system cells via CCL2 receptor.
Figure-2- Cross-section of a damaged liver tissue
Accumulated immune system cells secrete more cytokines like TNF- Alpha, Interleukin 6, interleukin- 1B and TGF, this is illustrated in figure 3.
Transforming growth factor (TGF) released primarily by stellate cells stimulate other stellate cells to transform myofibroblast thereby causing myofibroblast proliferation.
These myofibroblasts then release collagen in the matrix causing liver fibrosis.
Figure-3- Pathway to fibrosis
SIGNALING PATHWAYS FOR LIVER FIBROSIS –
Although there are several cell signaling mechanisms involved in the development of liver fibrosis, here we will discuss one of the signaling pathway that caffeine will block and there by prevent formation of fibers, which is andenosinergic signaling pathway which takes place in the myofibroblast cells of liver.
v ADENOSINERGIC PATHWAY- Adenosine triphosphate nucleotide present in the extracellular medium is dephosphorylated to form adenosine.
1. Consecutive removal of phosphate is carried out by enzymes like nucleoside triphosphate diphosphorylase (E – NTPDASE) family and ecto-5’-nucleotidase (E-5’-NT) family present on the surface of myofibroblast.
2. The formed adenosine then binds to four specific G- protein coupled receptor namely A1, A3, A2A, A2B. Binding of adenosine activates these receptors.
3. This binding and activation of these receptors leads to formation of adenylate cyclase and phospholipase C and modulation of downstream signaling pathways in the cytoplasm.
Figure-4- Step 1 of adenosinergic pathway- Formation of AC and PLC
Figure-5- Step 2 of adenosinergic pathway- Fate and role of AC and PLC inside the cell
4. Ecto - adenosine deaminase, another cell surface receptor, deaminates extracellular adenosine and removes it from circulation or it is taken up into the cell by equilibrative nucleoside transporter (ENT) or concentrative nucleoside transporters (CNT).
5. Increase in adenylate cyclase results in production of cyclic AMP (cAMP) in the cytoplasm.
6. cAMP stimulates production of protein kinase A, exchange proteins and several fibrogenic functions.
7. Also, A2A receptor regulates fibrogenic functions by governing the activity of phospholipase C (PLC) activity, calcium mobilization and protein Kinase C (PKC) activity.
8. In this way stimulation and initiation of this pathway results in production of fibers by myofibroblast cells.
HOW DOES COFFEE SUPPRESS THE COMPONENTS OF THE PATHWAY –
Caffeine (1,2,3 – Trimethylxanthine / C8H10N4O2) extracted from coffee were used on standard rodent models specifically manipulated by hepatotoxicants like dimethylnitrosamine (DMN), CCl4, or thioacetamide (TAA)to study liver fibrosis. And in every attempt, it was noted that coffee was successfully able to prevent liver fibrosis and cirrhosis in rodents. Also, in most of the work documented in this subject traditional filter coffee is used.
The mechanisms by which coffee is supposed to protect liver from fibrosis is as follows-
1. Caffeine has high affinity for A2A receptor as compared to ATP therefore in its presence it binds to A2A receptor and blokes the further downstream processing of cyclic AMP thereby preventing collagen secretion, chemotaxis, and stress fiber rearrangement. Hence no fiber is produced.
Figure-6- Action of Caffeine on A2A receptor of myofibroblast.
2. TGF- beta plays a major role in development and proliferation of liver fibrosis. It is a regulatory cytokine which is produced in large quantity from stellate when hepatocytes are damaged. Production of TGF – beta results in accumulation and activation of more stellate cells to differentiate and convert into myofibroblasts. But when rats administered with hepatotoxicants were given caffeine they did not show any signs or symptoms of fibrosis because caffeine reduces levels of TGF – beta.
Conclusion
Coffee is composed of a cocktail of chemical compounds that could be potentially antifibrotic. To answer this question lots of research work has been carried out by administrating decaffeinated coffee and caffeine solution to mice model systems but none of them were as efficient as an original coffee. This proves that there is still a lot to investigate about the effect of coffee on liver fibrosis. Although, it would be a bit early to credit caffeine for the effect improved liver condition on consumption of coffee, but there has been enough literature and research work done to believe that coffee is associated with hepatoprotective properties.
References-
1. Ryan d heath, Mihir Brahmbhatt, Asli C Tahan, Jamal A Ibdah, Veysel Tahan. 2017. Coffee: The magical bean for liver diseases. World journal of hepatology, 9(15): 689-696
2. Michel Fusther. 2018. Extracellular adenosine: a critical signal in liver fibrosis.
Am j physiol gastrointest liver physiol 315: g12–g19.
3. Apurva a. Modi, Jordan J. Feld, Yoon Park, David E. Kleiner, James E. Everhart, T. Jake Liang, and Jay H. Hoofnagle1. 2009. Wiley Interscience (www.interscience.wiley.com).
4. Jonathan A. Dranoff, Jordan J. Feld, Lise G. Lavoie, Michel Fausther. 2014. How does coffee prevent liver fibrosis?. Biological plausibility for recent epidemiological observations, hepatology: official journal of the american society for the study of liver disease, vol. 60, no. 2,
5. Simona-Rebeca Ignat, Sorina Dinescu, Anca Hermenean, and Marieta Costache. 2020. Cellular interplay as a consequence of inflammatory signals leading to liver fibrosis development. Cells 9(2): 461
6. Food Editorial. co
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