MicroRNAs (miRNAs) are small, non-coding RNA molecules, typically around 22 nucleotides long, that regulate gene expression after transcription. They bind to messenger RNA (mRNA) molecules, causing either the degradation of the mRNA or the repression of its translation into a protein. This mechanism allows the cell to fine-tune the amount of specific proteins produced.
Among the hundreds of miRNAs discovered, microRNA-122 (miR-122) is important due to its abundance and tissue specificity. In the adult liver, miR-122 accounts for up to 70% of the total microRNA pool, making it the most dominant regulator in this organ. This high concentration and liver-specific expression mean that miR-122 plays a central part in maintaining the normal physiological functions of the hepatocyte. Its influence extends beyond normal function into the development of major liver diseases, including metabolic disorders, viral infections, and cancer.
miR-122’s Role in Maintaining Healthy Liver Metabolism
The primary function of miR-122 in a healthy liver is maintaining metabolic balance, particularly involving fats and cholesterol. By regulating the expression of various enzymes and transport proteins, miR-122 helps sustain lipid homeostasis within the hepatocyte. This mechanism is crucial because the liver is the central organ for processing and distributing lipids.
Stable levels of miR-122 are necessary to control the synthesis and breakdown of fatty acids and cholesterol. Studies inhibiting miR-122 in animal models demonstrated a significant reduction in plasma cholesterol levels, suggesting that miR-122 promotes cholesterol production. It modulates genes involved in cholesterol biosynthesis, such as 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), a key control point in the pathway.
miR-122’s regulatory activities also prevent fat accumulation, a condition known as steatosis. When miR-122 is present at normal concentrations, it helps modulate the genes that govern fatty acid synthesis and oxidation. Its function is integral to preventing the excessive buildup of triglycerides within liver cells.
The metabolic control exerted by miR-122 helps maintain the liver’s specialized, differentiated state. When this control is lost, liver cells deviate from their normal metabolic profile, which can lead to chronic conditions like nonalcoholic steatohepatitis (NASH). The consistent expression of miR-122 is fundamental for preserving the metabolic health and structural integrity of the liver.
The Dual Role of miR-122 in Viral Hepatitis
The influence of miR-122 on viral infections demonstrates a complex interaction that varies depending on the specific virus. The most studied example is the Hepatitis C Virus (HCV), which exploits the abundance of miR-122 for its survival. HCV requires miR-122 to complete its life cycle within the host cell.
The virus possesses two specific binding sites for miR-122 within the 5′ untranslated region (UTR) of its RNA genome. Unlike the typical miRNA function of suppressing a target, miR-122 binding to the HCV genome promotes viral replication. This interaction stabilizes the viral RNA, protecting it from degradation by host nucleases, and stimulates the translation of viral proteins necessary for new virus production.
In contrast, miR-122 exhibits an inhibitory function against Hepatitis B Virus (HBV) replication. Research indicates that miR-122 can suppress HBV by targeting specific host genes or by interacting with the HBV pregenomic RNA. While high levels of miR-122 are exploited by HCV, they can be protective against HBV infection progression.
This creates a “dual role” for miR-122 in viral hepatitis: it acts as a host factor hijacked to promote HCV accumulation, yet simultaneously acts as an antiviral element against HBV. This distinction is important for developing targeted therapies that either block or enhance miR-122 activity depending on the viral pathogen.
miR-122 as a Key Player in Liver Cancer Progression
In the context of liver cancer, specifically Hepatocellular Carcinoma (HCC), miR-122 functions as a tumor suppressor, preventing the formation and spread of cancer. A hallmark of liver cancer is the frequent downregulation of miR-122 expression within the malignant tissue. This loss of expression is observed in approximately 70% of HCC cases and is associated with more aggressive tumors, metastasis, and a less favorable prognosis.
When miR-122 levels drop, its regulatory control over numerous target genes is released, allowing those genes to become highly active. These upregulated genes often include factors that promote cell proliferation, prevent apoptosis, and enhance the ability of cancer cells to invade surrounding tissues. For example, the loss of miR-122 leads to increased expression of proteins like ADAM17 and Cyclin G1, which drive cancer cell growth and migration.
The protective role of miR-122 is supported by studies where genetic deletion of miR-122 in animal models resulted in the spontaneous development of steatohepatitis, fibrosis, and tumors resembling HCC. This confirms that maintaining normal miR-122 levels is a fundamental mechanism for preventing the progression of chronic liver injury to malignancy. The suppression of miR-122 often occurs in the setting of chronic inflammation and fibrosis, suggesting a direct link between long-term liver damage and the loss of this protective mechanism.
Translating Knowledge into Diagnostic and Therapeutic Tools
The understanding of miR-122’s function in health and disease has led to its development as a valuable tool in clinical settings. One immediate application is as a non-invasive diagnostic biomarker for liver injury. Because miR-122 is abundant within hepatocytes, damage to these cells results in the rapid release of miR-122 into the bloodstream.
Circulating levels of miR-122 in the blood serum or plasma serve as a sensitive and specific indicator of liver cell damage, often rising earlier than traditional liver enzyme markers like transaminases. This makes it an effective tool for monitoring acute liver damage, such as drug-induced injury, and for assessing the severity and progression of chronic liver diseases. Its levels also show promise as a diagnostic marker for HCV-associated HCC, helping to distinguish between cancer and simple cirrhosis.
The unique and opposing roles of miR-122 in different diseases have positioned it as a direct therapeutic target. For conditions like HCV infection, where miR-122 is detrimental because it promotes viral replication, researchers developed anti-miRNA molecules to block its function. Miravirsen, the first miRNA-targeted therapeutic to enter clinical trials, demonstrated the viability of using anti-miRs to reduce viral load in patients.
Conversely, for diseases like HCC and NASH, where miR-122 levels are reduced and its tumor-suppressor function is lost, the strategy involves restoring its normal concentration. This is achieved using synthetic miR-122 mimics delivered to the liver, often encapsulated in specialized nanoparticles or viral vectors. This replacement strategy aims to reactivate the protective mechanisms of miR-122, inhibiting tumor growth and sensitizing cancer cells to conventional chemotherapy drugs like Sorafenib.