Introduction to microRNA-122

Regulating gene expression is essential to maintain the balance and functions of various systems in all living organisms. The microRNA (miRNA) molecules have emerged as significant contributors in that domain. First discovered in 1993 [1], these short, single-stranded RNA molecules (typically 21-23 bases) regulate gene expression by binding to specific regions of messenger RNA (mRNA) within the cell's cytoplasm. This binding either marks the mRNA for degradation or preserves it for future translation [2]. This way, a typical microRNA can modulate the expression and function of one or (usually) more genes.

Here, we will dive deeper into the intricate world of microRNAs, looking at microRNA-122 as a noteworthy example.

Background on microRNA-122

Within the family of microRNAs, miR-122 expression is tissue-specific: it is found predominantly in the liver and is virtually absent in other tissues in a healthy body. Moreover, it is the liver's most abundant miRNA, accounting for roughly 52% of its total microRNAs. But why does this specific microRNA bear such significance?

miR-122 plays a crucial role in diverse aspects of liver function:

• Cellular Dynamics: miR-122 is instrumental in the differentiation of hepatocytes, the primary cells in the liver [3]. Moreover, it also modulates genes like Cyclin G1 (CCNG1) and Bcl-w, vital players in cell cycle regulation and apoptosis. Through these interactions, miR-122 can drive hepatocyte proliferation and survival.
• Cholesterol and Lipid Metabolism: miR-122 governs genes such as HMGCR (3-hydroxy-3-methylglutaryl-CoA reductase), an important enzyme in the cholesterol biosynthesis pathway, and ALDOB (aldolase B). Consequently, suppressing miR-122 results in diminished cholesterol synthesis and altered lipid metabolism [4].
• Iron Homeostasis: miR-122 controls genes related to iron balance, such as HFE and HAMP (hepcidin). These genes critically influence iron absorption and storage, highlighting how alterations in their regulation can sway systemic iron levels [5].

The overarching theme is clear: miR-122 is a vital regulatory microRNA, especially considering liver metabolism and function. Notably, changes in miR-122 levels are widely recognised as a key sign of liver cell damage and have been studied extensively in various liver diseases.

microRNA-122 in Disease

The relevance of miR-122 extends beyond just metabolism; it intertwines with disease pathology as well: 

1. Chronic Liver Disease (NASH/NAFLD): Non-alcoholic steatohepatitis (NASH) and Non-Alcoholic Fatty Liver Disease (NAFLD) are chronic liver conditions that can progress to cirrhosis and liver failure. Studies have demonstrated altered levels of miR-122 in patients with NAFLD and NASH. Specifically, elevated miR-122 levels often correlate with liver fat content and inflammation, providing insight into the disease progression and severity. Moreover, miR-122 has been proposed to regulate lipid metabolism pathways disrupted in these conditions, underscoring its potential as both a diagnostic marker and a therapeutic target.
2. Acute Liver Injury: One common cause of acute liver injury is paracetamol (acetaminophen) overdose. In such cases, there's a marked release of miR-122 into the bloodstream due to liver damage. Therefore, elevated serum levels of miR-122 can serve as a rapid and sensitive biomarker for paracetamol-induced liver injury, enabling timely clinical intervention.
3. Oncogenesis: Research has unveiled miR-122's interactions with genes and pathways linked to tumorigenesis and metastasis, especially in hepatocellular carcinoma (HCC). For instance, the Wnt/β-catenin pathway, a key pathway implicated in cancer, is one such target. Alarmingly, reduced expression of miR-122 correlates with a more aggressive tumour phenotype in HCC.

Importance in Diagnostics

The central role miR-122 plays in various liver functions and pathologies highlights its potential in the diagnostic realm. Firstly, given its specificity to the liver and the fact that elevated levels in blood samples are indicative of liver injury or damage, it emerges as a reliable biomarker offering a glimpse into liver health and improved discrimination of disease states.

Furthermore, for conditions where miR-122 intricately intertwines with the disease mechanism, tracking its levels offers a window into the treatment's impact. By monitoring these levels, clinicians can gain insights into the efficacy of the therapeutic strategy, tweaking them if necessary for optimal patient outcomes. 

Finally, the expression patterns of miR-122 might hold prognostic insights as well. These patterns could provide early warnings, forecasting the onset or escalation of certain liver maladies. Such predictive power could be a game-changer, allowing for timely and pre-emptive interventions, potentially halting or at least mitigating the disease's progression.

Conclusions

miR-122 is a key diagnostic indicator of liver function and liver health. As our understanding of miR-122 deepens, so does its potential as a diagnostic biomarker and possibly a therapeutic agent in the future.

Are you working with microRNA-122?

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References

[1] Lee RC et al. “The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14.” Cell (1993)

[2] Shang R et al. “microRNAs in action: biogenesis, function and regulation.” Nature Reviews Genetics (2023)

[3] Deng XG et al. "Overexpression of miR-122 promotes the hepatic differentiation and maturation of mouse ESCs through a miR-122/FoxA1/HNF4a-positive feedback loop" Liver International (2014)

[4] Esau C et al. "miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting" Cell Metabolism (2006)

[5] Castoldi M et al. "The liver-specific microRNA miR-122 controls systemic iron homeostasis in mice" The Journal of Clinical Investigation (2011)