Function of Hepatocytes: Their Key Roles and Impact on Liver Research
The liver is a biochemical powerhouse, with hepatocytes at the heart of its many vital functions. These specialized cells play a crucial role in metabolism, detoxification, and regeneration, making them indispensable for both sustaining health and driving advancements in liver research.
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Functions of Liver Hepatocytes in Metabolism and Detoxification
Liver hepatocytes are involved in a wide array of biochemical processes that are essential for maintaining metabolic balance and protecting the body against toxins.
One of the primary functions of hepatocytes is the regulation of metabolism. They actively participate in gluconeogenesis, the synthesis of glucose from non-carbohydrate sources, which is crucial during fasting. Additionally, hepatocytes synthesize vital components such as albumin, other plasma proteins, cholesterol, and bile acids. They also regulate lipid metabolism through the oxidation of fatty acids, providing both energy and precursors for other metabolic pathways.
Detoxification process is another key function of hepatocytes, which metabolize drugs and toxins to render them less harmful and facilitate their excretion. This process occurs in three phases:
- Phase I involves enzymatic modifications, predominantly through the cytochrome P450 enzyme system located in the endoplasmic reticulum of hepatocytes, which introduces functional groups to make compounds more reactive. Cytochrome P450 enzymes, encoded by distinct genes, show activity variations among individuals due to genetic differences. Classified into families and subfamilies based on amino acid similarities, these enzymes reflect evolutionary specialization.
Of the many P450 enzymes in the liver, only a few, like CYP3A4, are crucial for drug detoxification, metabolizing approximately 50% of all therapeutic drugs.
- Phase II enhances the polarity of these substances through conjugation reactions such as glucuronidation and sulfation.
- Phase III involves the transport of these modified compounds out of the cells, either into bile for excretion via the gastrointestinal tract or into the blood for renal elimination.
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Hepatocyte Functions in Regeneration and Liver Research
Hepatocyte cells are not only critical for metabolic and detoxification processes but also play a central role in liver regeneration.
One of the liver’s defining features is its remarkable ability to self-repair, primarily driven by hepatocytes. Liver regeneration is initiated by the activation of Kupffer cells, which respond to the phagocytosis of damaged hepatocytes, or the presence of endotoxins carried through portal blood. Once activated, Kupffer cells release interleukin-6 (IL-6), priming resting hepatocytes to re-enter the cell cycle and proliferate. Additionally, Kupffer cells influence other liver cell types, such as stellate cells, to produce key growth factors like hepatocyte growth factor (HGF) and transforming growth factor-beta (TGF-β), both essential for hepatocyte proliferation and tissue remodeling during regeneration.
Human hepatocytes are pivotal for studying the dynamics of these regenerative processes and the molecular pathways involved. Primary human hepatocytes provide a relevant model for exploring how signaling pathways coordinate cellular responses during regeneration and how disruptions can lead to fibrosis or liver failure.
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What Are the Unique Features of Hepatocytes?
Hepatocytes possess several unique features that make them central to liver function and are critical for research. These cells make up the majority of liver volume and are surrounded by a highly vascularized system, facilitating constant exposure to blood flow for the exchange of nutrients and toxins. Hepatocytes in the liver exhibit distinct polarity with separate basolateral and apical domains in proximity composed of distinct surface protein channels and receptors. This allows them to perform simultaneously diverse functions such as protein secretion, bile production, and blood detoxification. Their sophisticated membrane trafficking machinery enables efficient transport of molecules to precise locations.
The cytochrome P450 enzyme system, a key player in detoxification, is a hallmark of hepatocytes. Its activity varies due to genetic differences and is further influenced by non-genetic factors, such as drug interactions and nutritional status, which can enhance or inhibit enzymatic activity. This variability affects how individuals metabolize drugs and toxins, with implications for therapeutic outcomes and susceptibility to toxic effects.
Using primary human hepatocytes in in vitro models is particularly valuable, as these cells retain the metabolic capabilities of their in vivo counterparts, including the genetic and functional diversity of the cytochrome P450 enzymes. This enables the faithful replication of metabolic and detoxification differences observed across populations. By incorporating primary human hepatocytes from diverse donors, these models account for interindividual and interpopulation variability, providing more accurate predictions of drug metabolism and toxicity.
BeCytes provides access to primary human hepatocytes derived from liver tissue discarded for transplantation. Fresh human hepatocytes for research purposes are obtained and isolated from a wide diversity of human donors. Cells are fully characterized, including liver-specific functions, the activities of drug transporters, and the induction of cytochrome P450 activities.
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References
Blondet NM, Messner DJ, Kowdley KV , Murray KF. Chapter 43 – Mechanisms of Hepatocyte Detoxification, Physiology of the Gastrointestinal Tract (Sixth Edition), Academic Press, 2018, Pages 981-1001, ISBN 9780128099544. doi.org:10.1016/B978-0-12-809954-4.00043-8.
Schulze RJ, Schott MB, Casey CA, Tuma PL, McNiven MA. The cell biology of the hepatocyte: A membrane trafficking machine. J Cell Biol. 2019 Jul 1;218(7):2096-2112. doi: 10.1083/jcb.201903090
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