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Current Biology : CB Nov 2017The liver is a critical hub for numerous physiological processes. These include macronutrient metabolism, blood volume regulation, immune system support, endocrine...
The liver is a critical hub for numerous physiological processes. These include macronutrient metabolism, blood volume regulation, immune system support, endocrine control of growth signaling pathways, lipid and cholesterol homeostasis, and the breakdown of xenobiotic compounds, including many current drugs. Processing, partitioning, and metabolism of macronutrients provide the energy needed to drive the aforementioned processes and are therefore among the liver's most critical functions. Moreover, the liver's capacities to store glucose in the form of glycogen, with feeding, and assemble glucose via the gluconeogenic pathway, in response to fasting, are critical. The liver oxidizes lipids, but can also package excess lipid for secretion to and storage in other tissues, such as adipose. Finally, the liver is a major handler of protein and amino acid metabolism as it is responsible for the majority of proteins secreted in the blood (whether based on mass or range of unique proteins), the processing of amino acids for energy, and disposal of nitrogenous waste from protein degradation in the form of urea metabolism. Over the course of evolution this array of hepatic functions has been consolidated in a single organ, the liver, which is conserved in all vertebrates. Developmentally, this organ arises as a result of a complex differentiation program that is initiated by exogenous signal gradients, cellular localization cues, and an intricate hierarchy of transcription factors. These processes that are fully developed in the mature liver are imperative for life. Liver failure from any number of sources (e.g. viral infection, overnutrition, or oncologic burden) is a global health problem. The goal of this primer is to concisely summarize hepatic functions with respect to macronutrient metabolism. Introducing concepts critical to liver development, organization, and physiology sets the stage for these functions and serves to orient the reader. It is important to emphasize that insight into hepatic pathologies and potential therapeutic avenues to treat these conditions requires an understanding of the development and physiology of specialized hepatic functions.
Topics: Amino Acids; Animals; Biological Transport; Energy Metabolism; Glucose; Glycogen; Hepatic Stellate Cells; Humans; Kupffer Cells; Lipid Metabolism; Liver; Obesity; Proteins
PubMed: 29112863
DOI: 10.1016/j.cub.2017.09.019 -
Cells Mar 2020The mitochondrion is an organelle that plays a vital role in the regulation of hepatic cellular redox, lipid metabolism, and cell death. Mitochondrial dysfunction is... (Review)
Review
The mitochondrion is an organelle that plays a vital role in the regulation of hepatic cellular redox, lipid metabolism, and cell death. Mitochondrial dysfunction is associated with both acute and chronic liver diseases with emerging evidence indicating that mitophagy, a selective form of autophagy for damaged/excessive mitochondria, plays a key role in the liver's physiology and pathophysiology. This review will focus on mitochondrial dynamics, mitophagy regulation, and their roles in various liver diseases (alcoholic liver disease, non-alcoholic fatty liver disease, drug-induced liver injury, hepatic ischemia-reperfusion injury, viral hepatitis, and cancer) with the hope that a better understanding of the molecular events and signaling pathways in mitophagy regulation will help identify promising targets for the future treatment of liver diseases.
Topics: Animals; Humans; Liver; Liver Diseases; Mitochondria; Mitophagy; Receptors, Cell Surface; Signal Transduction
PubMed: 32244304
DOI: 10.3390/cells9040837 -
Biochimica Et Biophysica Acta.... May 2019The size of the liver of terrestrial mammals obeys the allometric scaling law over a weight range of >3 ∗ 10. Since scaling reflects adaptive changes in size or... (Review)
Review
The size of the liver of terrestrial mammals obeys the allometric scaling law over a weight range of >3 ∗ 10. Since scaling reflects adaptive changes in size or scale among otherwise similar animals, we can expect to observe more similarities than differences between rodent and human livers. Obvious differences, such as the presence (rodents) or absence (humans) of lobation and the presence (mice, humans) or absence (rats) of a gallbladder, suggest qualitative differences between the livers of these species. After review, however, we conclude that these dissimilarities represent relatively small quantitative differences. The microarchitecture of the liver is very similar among mammalian species and best represented by the lobular concept, with the biggest difference present in the degree of connective tissue development in the portal tracts. Although larger mammals have larger lobules, increasing size of the liver is mainly accomplished by increasing the number of lobules. The increasing role of the hepatic artery in lobular perfusion of larger species is, perhaps, the most important and least known difference between small and large livers, because it profoundly affects not only interventions like liver transplantations, but also calculations of liver function.
Topics: Animals; Biological Evolution; Gallbladder; Humans; Liver; Rodentia
PubMed: 29842921
DOI: 10.1016/j.bbadis.2018.05.019 -
Development, Growth & Differentiation Jan 2021The human adult liver has a multi-cellular structure consisting of large lobes subdivided into lobules containing portal triads and hepatic cords lined by specialized... (Review)
Review
The human adult liver has a multi-cellular structure consisting of large lobes subdivided into lobules containing portal triads and hepatic cords lined by specialized blood vessels. Vital hepatic functions include filtering blood, metabolizing drugs, and production of bile and blood plasma proteins like albumin, among many other functions, which are generally dependent on the location or zone in which the hepatocyte resides in the liver. Due to the liver's intricate structure, there are many challenges to design differentiation protocols to generate more mature functional hepatocytes from human stem cells and maintain the long-term viability and functionality of primary hepatocytes. To this end, recent advancements in three-dimensional (3D) stem cell culture have accelerated the generation of a human miniature liver system, also known as liver organoids, with polarized epithelial cells, supportive cell types and extra-cellular matrix deposition by translating knowledge gained in studies of animal organogenesis and regeneration. To facilitate the efforts to study human development and disease using in vitro hepatic models, a thorough understanding of state-of-art protocols and underlying rationales is essential. Here, we review rapidly evolving 3D liver models, mainly focusing on organoid models differentiated from human cells.
Topics: Cell Culture Techniques; Cell Differentiation; Hepatocytes; Humans; Liver; Models, Biological; Organoids
PubMed: 33423319
DOI: 10.1111/dgd.12708 -
Comprehensive Physiology Apr 2013The liver is the largest organ in the body and is generally regarded by nonimmunologists as having little or no lymphoid function. However, such is far from accurate.... (Review)
Review
The liver is the largest organ in the body and is generally regarded by nonimmunologists as having little or no lymphoid function. However, such is far from accurate. This review highlights the importance of the liver as a lymphoid organ. Firstly, we discuss experimental data surrounding the role of liver as a lymphoid organ. The liver facilitates tolerance rather than immunoreactivity, which protects the host from antigenic overload of dietary components and drugs derived from the gut and it is instrumental to fetal immune tolerance. Loss of liver tolerance leads to autoaggressive phenomena, which if not controlled by regulatory lymphoid populations, may lead to the induction of autoimmune liver diseases. Liver-related lymphoid subpopulations also act as critical antigen-presenting cells. The study of the immunological properties of liver and delineation of the microenvironment of the intrahepatic milieu in normal and diseased livers provides a platform to understand the hierarchy of a series of detrimental events that lead to immune-mediated destruction of the liver and the rejection of liver allografts. The majority of emphasis within this review will be on the normal mononuclear cell composition of the liver. However, within this context, we will discuss selected, but not all, immune-mediated liver disease and attempt to place these data in the context of human autoimmunity.
Topics: Animals; Antigen-Presenting Cells; Humans; Immune Tolerance; Immunity, Humoral; Liver; Liver Diseases
PubMed: 23720323
DOI: 10.1002/cphy.c120011 -
JCI Insight Nov 2020Adult liver has enormous regenerative capacity; it can regenerate after losing two-thirds of its mass while sustaining essential metabolic functions. How the liver...
Adult liver has enormous regenerative capacity; it can regenerate after losing two-thirds of its mass while sustaining essential metabolic functions. How the liver balances dual demands for increased proliferative activity with maintenance of organ function is unknown but essential to prevent liver failure. Using partial hepatectomy (PHx) in mice to model liver regeneration, we integrated single-cell RNA- and ATAC-Seq to map state transitions in approximately 13,000 hepatocytes at single-cell resolution as livers regenerated, and validated key findings with IHC, to uncover how the organ regenerates hepatocytes while simultaneously fulfilling its vital tissue-specific functions. After PHx, hepatocytes rapidly and transiently diversified into multiple distinct populations with distinct functional bifurcation: some retained the chromatin landscapes and transcriptomes of hepatocytes in undamaged adult livers, whereas others transitioned to acquire chromatin landscapes and transcriptomes of fetal hepatocytes. Injury-related signaling pathways known to be critical for regeneration were activated in transitioning hepatocytes, and the most fetal-like hepatocytes exhibited chromatin landscapes that were enriched with transcription factors regulated by those pathways.
Topics: Animals; Biomarkers; Cell Proliferation; Hepatocytes; Liver; Liver Regeneration; Male; Mice; Mice, Inbred C57BL; Signal Transduction; Single-Cell Analysis
PubMed: 33208554
DOI: 10.1172/jci.insight.141024 -
International Journal of Surgery... Oct 2020A dilemma of graft selection between right or left livers occurs during the planning of living-donor liver transplantation (LDLT) as well as splitting a whole liver...
A dilemma of graft selection between right or left livers occurs during the planning of living-donor liver transplantation (LDLT) as well as splitting a whole liver graft into full right/full left grafts in deceased-donor liver transplantation. The right liver's relation to the whole liver could be considered as the trunk of a tree; it has a larger volume, the main axis of bile ducts, and the inferior vena cava mainly belongs to the right liver. Therefore, it was considered as the standard graft in LDLTs. Whether to procure the middle hepatic vein (MHV) with a right liver graft or to leave it attached to the left-liver remnant largely depends on the transplant institute. Recently, most transplant institutes tend to leave the MHV with the left liver for the sake of donor safety. Unlike hepatectomy for liver tumors, it is vital to preserve inflow and outflow for both the resected as well as the remaining livers. While procuring any graft type, the most important is to procure a liver graft with reconstructable portal veins, hepatic arteries, hepatic veins, and bile ducts, which should be well preoperatively planned using 3D-computed tomography with considerations given to graft volume and potential congestion areas.
Topics: Adult; Female; Hepatectomy; Hepatic Artery; Hepatic Veins; Humans; Liver; Liver Transplantation; Living Donors; Male; Middle Aged; Portal Vein; Tissue and Organ Harvesting; Transplants; Vena Cava, Inferior
PubMed: 32619620
DOI: 10.1016/j.ijsu.2020.06.022 -
Cells Nov 2023Mature hepatocytes (MHs) in an adult rodent liver are categorized into the following three subpopulations based on their proliferative capability: type I cells (MH-I),... (Review)
Review
Mature hepatocytes (MHs) in an adult rodent liver are categorized into the following three subpopulations based on their proliferative capability: type I cells (MH-I), which are committed progenitor cells that possess a high growth capability and basal hepatocytic functions; type II cells (MH-II), which possess a limited proliferative capability; and type III cells (MH-III), which lose the ability to divide (replicative senescence) and reach the final differentiated state. These subpopulations may explain the liver's development and growth after birth. Generally, small-sized hepatocytes emerge in mammal livers. The cells are characterized by being morphologically identical to hepatocytes except for their size, which is substantially smaller than that of ordinary MHs. We initially discovered small hepatocytes (SHs) in the primary culture of rat hepatocytes. We believe that SHs are derived from MH-I and play a role as hepatocytic progenitors to supply MHs. The population of MH-I (SHs) is distributed in the whole lobules, a part of which possesses a self-renewal capability, and decreases with age. Conversely, injured livers of experimental models and clinical cases showed the emergence of SHs. Studies demonstrate the involvement of SHs in liver regeneration. SHs that appeared in the injured livers are not a pure population but a mixture of two distinct origins, MH-derived and hepatic-stem-cell-derived cells. The predominant cell-derived SHs depend on the proliferative capability of the remaining MHs after the injury. This review will focus on the SHs that appeared in the liver and discuss the significance of SHs in liver regeneration.
Topics: Rats; Animals; Rats, Inbred F344; Liver; Hepatocytes; Cell Differentiation; Stem Cells; Mammals
PubMed: 38067145
DOI: 10.3390/cells12232718 -
Annual Review of Physiology 2015The mammalian liver is one of the most regenerative tissues in the body, capable of fully recovering mass and function after a variety of injuries. This factor alone... (Review)
Review
The mammalian liver is one of the most regenerative tissues in the body, capable of fully recovering mass and function after a variety of injuries. This factor alone makes the liver unusual among mammalian tissues, but even more atypical is the widely held notion that the method of repair depends on the manner of injury. Specifically, the liver is believed to regenerate via replication of existing cells under certain conditions and via differentiation from specialized cells--so-called facultative stem cells--under others. Nevertheless, despite the liver's dramatic and unique regenerative response, the cellular and molecular features of liver homeostasis and regeneration are only now starting to come into relief. This review provides an overview of normal liver function and development and focuses on the evidence for and against various models of liver homeostasis and regeneration.
Topics: Animals; Cell Differentiation; Cell Proliferation; Hepatocytes; Homeostasis; Humans; Liver; Liver Diseases; Liver Regeneration; Stem Cells
PubMed: 25668020
DOI: 10.1146/annurev-physiol-021113-170255 -
Cellular & Molecular Immunology May 2016The liver represents a frontline immune organ that is constantly exposed to a variety of gut-derived antigens as a result of its unique location and blood supply. With a... (Review)
Review
The liver represents a frontline immune organ that is constantly exposed to a variety of gut-derived antigens as a result of its unique location and blood supply. With a predominant role in innate immunity, the liver is enriched with various innate immune cells, among which natural killer (NK) cells play important roles in host defense and in maintaining immune balance. Hepatic NK cells were first described as 'pit cells' in the rat liver in the 1970s. Recent studies of NK cells in mouse and human livers have shown that two distinct NK cell subsets, liver-resident NK cells and conventional NK (cNK) cells, are present in this organ. Here, we review liver NK cell subsets in different species, revisiting rat hepatic pit cells and highlighting recent progress related to resident NK cells in mouse and human livers, and also discuss the dual roles of NK cells in liver immunity.
Topics: Animals; Humans; Immune Tolerance; Immunity, Innate; Killer Cells, Natural; Liver
PubMed: 26639736
DOI: 10.1038/cmi.2015.96