Materiały źródłowe

• #1 Pathogenesis of Alcoholic Liver Disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4933837/

  Alcoholic Liver Disease includes a broad clinical-histological spectrum from simple steatosis, cirrhosis, acute alcoholic hepatitis with or without cirrhosis to hepatocellular carcinoma as a complication of cirrhosis. The pathogenesis of ALD can be conceptually divided into 1) Ethanol mediated liver injury, 2) Inflammatory Immune response to injury, 3) Intestinal permeability and microbiome changes. […] Alcohol contributes to liver injury through a multitude of ways as depicted. Alcohol is metabolized to acetaldehyde; both alcohol and acetaldehyde have toxic effects on hepatocytes. Damaged hepatocytes in turn release DAMPs that recruit innate and adaptive immune cells that perpetuate further liver injury. […] Alcohol metabolism leads to oxidative stress and hepatocyte death. Damaged hepatocytes release endogenous DAMPs, which are usually hidden from the extracellular environment. DAMPs activate cellular pattern recognition receptors, which results in sterile inflammation.

• #2 Pathogenesis of liver cirrhosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4064077/

  Liver cirrhosis is the final pathological result of various chronic liver diseases, and fibrosis is the precursor of cirrhosis. Many types of cells, cytokines and miRNAs are involved in the initiation and progression of liver fibrosis and cirrhosis. Activation of hepatic stellate cells (HSCs) is a pivotal event in fibrosis. Defenestration and capillarization of liver sinusoidal endothelial cells are major contributing factors to hepatic dysfunction in liver cirrhosis. Activated Kupffer cells destroy hepatocytes and stimulate the activation of HSCs. Repeated cycles of apoptosis and regeneration of hepatocytes contribute to pathogenesis of cirrhosis. At the molecular level, many cytokines are involved in mediation of signaling pathways that regulate activation of HSCs and fibrogenesis. Recently, miRNAs as a post-transcriptional regulator have been found to play a key role in fibrosis and cirrhosis. Robust animal models of liver fibrosis and cirrhosis, as well as the recently identified critical cellular and molecular factors involved in the development of liver fibrosis and cirrhosis will facilitate the development of more effective therapeutic approaches for these conditions.

• #3 Pathogenesis of Liver Injury and Hepatic Failure | SpringerLink

  https://link.springer.com/chapter/10.1007/978-981-15-5984-6_6

  The liver is one of the most important organs of the human body, with a variety of complex functions including synthesis, detoxification, metabolism, secretion, biotransformation, and immune defense. […] Liver failure can occur when severe damage is caused by a variety of factors, such as viruses, hepatotoxic substances, and drugs. […] According to the clinical, pathological, and molecular biological changes of the disease, the patients with liver failure have experienced three injuries including direct injury, immune response, and endotoxemia. […] In order to better understand the specific characteristics of the occurrence and development of liver failure, in this chapter, we describe in detail the specific mechanisms of liver failure caused by common liver damage, as well as the pathophysiological manifestations of different stages of liver failure.

• #4 Pathogenesis of liver cirrhosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4064077/

  Although the causes of liver cirrhosis are multifactorial, there are some pathological characteristics that are common to all cases of liver cirrhosis, including degeneration and necrosis of hepatocytes, and replacement of liver parenchyma by fibrotic tissues and regenerative nodules, and loss of liver function. Fibrosis as a precursor of cirrhosis is a pivotal pathological process in the evolution of all chronic liver diseases to cirrhosis. […] Thus, a better understanding of the pathogenesis of liver cirrhosis would facilitate the development of more effective treatment options. […] HSC activation is a pivotal event in initiation and progression of hepatic fibrosis and a major contributor to collagen deposition. Activation of HSCs is characterized by cell proliferation and migration, contraction after transforming into myofibroblasts, generation of a large amount of collagen and other extracellular matrix (ECM), ultimately leading to liver fibrosis.

• #5 Pathogenesis of Alcoholic Liver Disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4933837/

  Steatosis is characterized by the accumulation of triglycerides, phospholipids, and cholesterol esters in hepatocytes. An early study attributed steatosis to the increased ratio of reduced nicotinamide adenine dinucleotide to oxidized nicotinamide adenine dinucleotide, which inhibits -oxidation of fatty acids in mitochondria. Recent studies have indicated that alcohol consumption regulates lipid metabolism transcription factors. […] Chronic alcohol leads to lipid peroxidation. Lipid peroxidation products, such as malondialdehyde and 4-hydroxynonenal, can form protein adducts and serve as antigens to activate adaptive immunity. […] The leading cause of death in AH is overwhelming bacterial infection, leading to multiorgan failure. Paradoxically, immune activity is heightened with inflammation.

• #6 Pathogenic mechanisms and regulatory factors involved in alcoholic liver disease | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-04166-8

  Alcohol-induced liver injury mainly involves structural damage to liver cells, lipid accumulation, and inflammation. Studies have demonstrated that transcription factors, kinases, and microRNAs (miRNAs) play critical regulatory roles in ALD. […] Several mechanisms are possibly associated with ethanol-induced liver diseases. For example, acute ethanol consumption can result in oxidative stress, nitrification stress, endoplasmic reticulum (ER) stress, inflammation, and apoptosis. Chronic ethanol consumption can result in dysregulated lipid metabolism, lipid accumulation, and AFL and alter the gut-liver axis by damaging the tightly connective structures of the intestinal epithelium. […] Ethanol exposure can reduce mitochondrial volume and the F0 adenosine triphosphate (ATP) synthase levels and inhibit protein synthesis. Ethanol metabolism can also disrupt the phospholipid bilayer membrane structure of mitochondria, resulting in the release of a large number of oxygen free radicals, lipid peroxidation, unsaturated FA destruction, and the production of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE).

• #7 Pathogenesis of liver cirrhosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4064077/

  Defenestration and capillarization of the hepatic endothelium are believed to be important in the initiation of perisinusoidal fibrosis by altering retinol metabolism. Studies in animals and humans have revealed that LSECs can secrete the cytokine IL-33 to activate HSCs and promote fibrosis. […] KCs can be activated by many injurious factors such as viral infection, alcohol, high-fat diet, and iron deposition. Activated KCs destroy hepatocytes by producing harmful soluble mediators and serving as antigen-presenting cells during viral infection. […] Hepatocytes are the primary liver parenchymal cells, and play complicated roles in fibrosis and cirrhosis. Hepatocytes are targets for most hepatotoxic agents, including hepatitis viruses, alcohol metabolites, and bile acids. […] Chronic liver diseases either promotes apoptosis or trigger compensatory regeneration of hepatocytes.

• #8 Pathogenic mechanisms and regulatory factors involved in alcoholic liver disease | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-04166-8

  Ethanol oxidation leads to an increase in free radical production in the liver. Uncontrolled ROS are critical to hepatocyte swelling and apoptosis. […] Excessive ROS can alter the function of glutathione (GSH) transporter channels, leading to progressive GSH deficiency in mitochondria and inactivation of oxidative phosphorylase, resulting in an irregular mitochondrial shape, decreases in mitochondrial protein synthesis, and altered ATP production in mitochondria. […] The main enzymes related to nitrification stress are two subtypes of NO synthase (NOS): endothelial NOS (eNOS) and inducible NOS (iNOS). Under physiological conditions, eNOS is abundant in the liver, whereas the iNOS level is barely detectable. […] Sustained ER stress may lead to cell and tissue damage. […] Ethanol can trigger the ER stress response, which is followed by the stimulation of apoptosis-related gene expression, cell proliferation, and apoptosis imbalance.

• #9 Non-Alcoholic Fatty Liver Disease: Pathogenesis and the Significance of High-Density Lipoprotein as a Molecular Modifier | IntechOpen

  https://www.intechopen.com/chapters/84460

  Several factors, including oxidative stress, insulin resistance, steatohepatitis, endoplasmic reticulum stress, bacterial overgrowth, fibrosis, genetic implications, immune system, and beverages consumption, have been implicated in the progress of NAFLD. […] The influences of oxidative stress and mitochondrial dysfunction in NAFLD and NASH are well-recognized. […] Oxidative stress has progressively shown to be one of the major essential pathological processes in the development of NAFLD and the relationship between NASH manifestation and simple steatosis. […] Endoplasmic reticulum (ER) stress is another pathway associated with the pathophysiology of NAFLD and NASH. […] Insulin resistance is among the major causes of NAFLD, which increases hepatic lipogenesis and inhibits adipose tissue lipolysis, resulting in an enhanced influx of fatty acids into the liver.

• #10 Pathogenic mechanisms and regulatory factors involved in alcoholic liver disease | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-04166-8

  Alcoholism is a widespread and damaging behaviour of people throughout the world. Long-term alcohol consumption has resulted in alcoholic liver disease (ALD) being the leading cause of chronic liver disease. […] Therefore, the underlying mechanisms of ALD are complex, involving inflammation, mitochondrial damage, endoplasmic reticulum stress, nitrification, and oxidative stress. Moreover, recent evidence has demonstrated that the gut-liver axis plays a critical role in ALD pathogenesis. […] Although ethanol-induced liver injury has been of great concern in recent years, the underlying mechanisms of ethanol-induced liver injury are complex and involve multiple signaling pathways. Therefore, understanding these mechanisms is of great importance for the development of improved ALD treatments.

• #11 Pathogenesis of Alcoholic Liver Disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4933837/

  Alcoholic liver disease is associated with bacterial overgrowth and a lower proportion of Bacteroidaceae and probiotic bacteria such as Lactobacillus. […] Zinc deficiency is common in ALD. Animal models have demonstrated that zinc deficiency attenuates alcohol-induced liver injury through various mechanisms, but most importantly, zinc deficiency impairs the intestinal barrier, leading to endotoxin-induced cytokine production. […] Usually, liver damage induces mature hepatocytes to proliferate and replace damaged tissue. Given massive or chronic liver damage that is beyond the proliferative capacity of hepatocytes, progenitor cells proliferate to produce a ductular reaction. […] The general mechanism for the development of HCC includes i) limitation of the regenerative reserve and induction of chromosomal instability by telomeres, ii) cancer induction by the loss of replicative competition due to impaired hepatocyte proliferation, iii) an altered microenvironment promoting tumor cell proliferation, and 4) the loss of cell cycle check point, including resistance to apoptosis and activation of oncogenic pathways.

• #12 Pathogenic mechanisms and regulatory factors involved in alcoholic liver disease | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-04166-8

  The intake of a large amount of ethanol induces the expression of ASS, which enzymatically activates the nitrification stress response and apoptosis in liver cells. […] The translocation of bacterial or microbial products from the intestine to the liver is a key inflammatory factor that induces the transition from alcoholic steatosis to ASH. […] Ethanol exposure results in the loss of epithelial cells at the tip of intestinal villi. […] After long-term ethanol intake, the intestinal epithelial cell structure in rats is markedly changed, exhibiting mitochondrial and endoplasmic reticulum dilation. […] The oxidative stress initiated by ethanol led to the oxidation of cytoskeletal microtubules and TJ decomposition. […] The oxidative metabolite of ethanol, acetaldehyde, is highly toxic and can readily undergo crosslinking with DNA or protein macromolecules in mitochondria.

• #13 The Role of Cytokines in the Pathogenesis and Treatment of Alcoholic Liver Disease

  https://www.mdpi.com/2079-9721/12/4/69

  The pathogenesis of ALD is multifactorial and not fully elucidated due to complex mechanisms related to direct ethanol toxicity with subsequent hepatic and systemic inflammation. […] The pathogenesis of ALD is based on multiple and complex molecular mechanisms that are not yet fully elucidated. These include direct ethanol hepatotoxicity, lipid peroxidation, oxidative stress with consequent ROS production, activation of the immune response, and activation of proinflammatory cytokines. […] Chronic alcohol consumption is involved in the accumulation of intestinal endotoxins and increased permeability of the intestinal wall, facilitating the translocation of lipopolysaccharide (LPS) from the gut to the liver. […] The different pathogenetic pathways involved in ALD development are summarized in Figure 1.

• #14 Steatotic liver disease – Symptoms, diagnosis and treatment | BMJ Best Practice US

  https://bestpractice.bmj.com/topics/en-us/796

  Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the most common causes of chronic liver disease in the developed world. […] It is a spectrum of disease, ranging from hepatic fat accumulation without inflammation to steatohepatitis, fibrosis, cirrhosis, and end-stage liver disease. […] MASLD is considered the hepatic manifestation of metabolic syndrome and is associated with obesity, dyslipidemia, and type 2 diabetes mellitus. […] The diagnosis of MASLD is based on exclusion of other etiologies of steatotic liver disease, such as alcohol use, and supportive laboratory tests and imaging. […] Liver biopsy and histology is the gold standard for diagnosis, and is performed for patients at higher risk of fibrosis or steatohepatitis. […] Pure MASLD encompasses patients with SLD and at least one of five cardiometabolic risk factors.

• #15 Fatty liver disease – Wikipedia

  https://en.wikipedia.org/wiki/Fatty_liver_disease

  Fatty liver (FL) is commonly associated with metabolic syndrome (diabetes, hypertension, obesity, and dyslipidemia), but can also be due to any one of many causes. […] Defects in fatty acid metabolism are responsible for pathogenesis of FLD, which may be due to imbalance in energy consumption and its combustion, resulting in lipid storage, or can be a consequence of peripheral resistance to insulin, whereby the transport of fatty acids from adipose tissue to the liver is increased. […] Impairment or inhibition of receptor molecules (PPAR-, PPAR- and SREBP1) that control the enzymes responsible for the oxidation and synthesis of fatty acids appears to contribute to fat accumulation. […] On the other hand, non-alcoholic FLD may begin as excess of unmetabolised energy in liver cells. […] Severe fatty liver is sometimes accompanied by inflammation, a situation referred to as steatohepatitis.

• #16 Multiple organs involved in the pathogenesis of non-alcoholic fatty liver disease | Cell & Bioscience | Full Text

  https://cellandbioscience.biomedcentral.com/articles/10.1186/s13578-020-00507-y

  The initiating events in NAFLD arise from the development of obesity and IR at the level of the adipose tissue and liver. The dysregulation of peripheral lipolysis, DNL, and dietary fat cause the increased FFA flux within the liver and then place hepatocytes under the lipotoxic condition. These lipotoxic FFAs are partitioned into inert intracellular triacylglycerol (TAG) for storage via acyl-CoA synthetic activity and mitochondrial -oxidation, and the accumulation of TAG in hepatocyte cytoplasm, which is also called steatosis, is the generally accepted histological hallmark of NAFLD. Many patients could stay in the NAFL stage for years, while the chronic insults would ultimately exceed the hepatic capacity to deal with the overload of fatty acids (FA). Significant hepatocyte injury leads to cell injury and inflammation, subsequently bringing Kupffer cells and other immune cells to the battlefield. Uncontrollable lipotoxicity facilitates ROS formation, ER stress, and hepatocellular dysfunction. Immune and apoptotic pathway activation results in cell death, which further drives fibrosis development over time.

• #17 Pathogenesis and pathways: nonalcoholic fatty liver disease & alcoholic liver disease – Robinson – Translational Gastroenterology and Hepatology

  https://tgh.amegroups.org/article/view/5734/html

  NAFLD has both environmental and genetic components. […] Insulin resistance correlates strongly with the development of nonalcoholic hepatic steatosis and causes profound changes to normal systemic lipid metabolism. […] How the buildup of lipids within the liver leads to the hepatocellular injury seen in nonalcoholic steatohepatitis remains a matter of debate. […] Hepatic iron content may also contribute to the oxygen free radical damage seen in NASH. […] The gut microbiome may contribute to the pathogenesis of NAFLD in a similar manner to its contribution in ALD. […] ALD and NAFLD are complex multifactorial disorders, and the understanding of their pathogenesis remains incomplete.

• #18 Multiple organs involved in the pathogenesis of non-alcoholic fatty liver disease | Cell & Bioscience | Full Text

  https://cellandbioscience.biomedcentral.com/articles/10.1186/s13578-020-00507-y

  Two important enzyme systems, acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), play vital roles in Hepatic FA synthesis. Insulin and glucose could regulate both enzymes by activating sterol regulatory element-binding protein 1c (SREBP-1c) and carbohydrate-responsive element-binding protein (ChREBP), two important transcriptional factors in DNL, respectively. Liver X receptor (LXR), a nuclear receptor, also directly controls the activity of both SREBP-1c and ChREBP by binding to response elements in the promoters of genes. Deletion of LXR leads to decreased SREBP-1c expression and less lipogenesis in mice. The induction effects of LXR on ACC and FAS could also be indirectly influenced by insulin and glucose. As hyperinsulinemia and hyperglycemia is commonly seen in NAFLD population, the link between glucose and lipid metabolism is conspicuous. Excess glucose is usually stored as glycogen, mediated by insulin, while it could also be esterified into TAGs via DNL. Hepatic IR in NAFLD is found mediated by proinflammatory cytokines, ER stress, apoptosis pathways, and even lipid metabolites. Accumulation of diacylglycerol (DAG), a lipotoxic intermediate of FA synthesis, within cytosolic lipid droplets induces translocation of protein kinase C (PKC)- to the plasma membrane and inhibits the intracellular kinase domain of the insulin receptor. In a NAFLD cohort, DAG content and PKC activation are the most significant predictors for hepatic IR and associate with 60% of the variability in hepatic insulin sensitivity.

• #19 Multiple organs involved in the pathogenesis of non-alcoholic fatty liver disease | Cell & Bioscience | Full Text

  https://cellandbioscience.biomedcentral.com/articles/10.1186/s13578-020-00507-y

  Specifically, for NAFLD, the persistence of liver steatosis derives from the overload of free fatty acids (FFAs) influx, which is the coefficient result of high fat diet, obesity, IR, gut microbiota alteration, and other potential risk factors. Furthermore, high levels of FFAs will exert the lipotoxic effects, causing endoplasmic reticulum (ER) stress and mitochondrial dysfunction (oxidative stress, production of reactive oxygen species (ROS), etc.) in the liver. IR not only motivates hepatic de novo lipogenesis (DNL), but also causes adipose tissue dysfunction with consequent adipokines and inflammatory cytokines production. Gut microbiota dysregulation could lead to the increase of intestine permeability and the release of proinflammatory cytokines into circulation. Multiple pathways synergistically create a vicious cycle which slowly exacerbates the disbalance of liver homeostasis and induces the shift from simple steatosis to chronic inflammatory state of NASH. Based on evidences above, NAFLD is definitely not a single-organ disease, but more like the hepatic manifestation of a variety of complicated metabolic disorders involving different organs and systems.

• #20 Pathogenesis of liver cirrhosis

  https://www.wjgnet.com/1007-9327/coretip/v20/i23/7312.htm

  Cirrhosis is the end-stage condition of many types of chronic liver diseases but the underlying mechanisms are far from being clarified. Multiple cellular and molecular factors might be involved in the initiation and progression of cirrhosis. Activation of hepatic stellate cells is a pivotal event in the development of cirrhosis. […] Animal models are crucial for understanding the pathogenesis and the development of more efficient therapeutic strategies for cirrhosis, with which cirrhosis may become a treatable or even a reversible disease.

• #21 Pathogenesis of liver cirrhosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4064077/

  Apoptosis of hepatocytes is a common event in liver injury and contributes to tissue inflammation, fibrogenesis, and development of cirrhosis. […] TGF- is the strongest known inducer of fibrogenesis in hepatic fibrosis. […] The pro-fibrogenesis effect of TGF-1 is complicated, involving multiple aspects: the primary effect of TGF-1 is to stimulate activation of HSCs, and the TGF-1 autocrine loop in activated HSCs is an important positive feedback to the progression of liver fibrosis. […] Given the critical role of TGF-1 in the pathogenesis of liver cirrhosis, specific blockade of TGF-1/Smad3 signaling has shown some therapeutic value for liver fibrosis. […] It is now thought that miRNAs can serve as biomarkers for HSC activation and liver fibrosis progression, and may represent therapeutic targets for hepatic fibrosis and cirrhosis.

• #22 Pathogenesis of liver cirrhosis

  https://wjgnet.com/1007-9327/abstract/v20/i23/7312.htm

  Liver cirrhosis is the final pathological result of various chronic liver diseases, and fibrosis is the precursor of cirrhosis. Many types of cells, cytokines and miRNAs are involved in the initiation and progression of liver fibrosis and cirrhosis. Activation of hepatic stellate cells (HSCs) is a pivotal event in fibrosis. Defenestration and capillarization of liver sinusoidal endothelial cells are major contributing factors to hepatic dysfunction in liver cirrhosis. Activated Kupffer cells destroy hepatocytes and stimulate the activation of HSCs. Repeated cycles of apoptosis and regeneration of hepatocytes contribute to pathogenesis of cirrhosis. At the molecular level, many cytokines are involved in mediation of signaling pathways that regulate activation of HSCs and fibrogenesis. Recently, miRNAs as a post-transcriptional regulator have been found to play a key role in fibrosis and cirrhosis.

• #23 Liver disease pathophysiology – The Pharmaceutical Journal

  https://pharmaceutical-journal.com/article/ld/liver-disease-pathophysiology

  Liver fibrosis refers to the accumulation of tough, fibrous scar tissue in the liver. The necrosis of hepatocytes stimulates immune cells to release cytokines, growth factors and various unknown chemicals. These chemical messengers direct hepatic stellate cells (support cells in the liver) to activate and produce collagen, glycoproteins (such as fibronectin) and proteoglycans among other substances. These substances are deposited in the liver, causing the build-up of non-functional connective tissue, termed “extracellular matrix”. […] Liver fibrosis can become so extensive that the architecture of the liver is altered — this is called cirrhosis. As cirrhosis develops, scar tissue replaces healthy liver cells. The usual smooth texture of the liver becomes nodular causing the free flow of blood throughout it to be compromised, thus reducing the ability of the liver to perform its many functions.

• #24 Esophageal varices – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/esophageal-varices/symptoms-causes/syc-20351538

  Esophageal varices most often happen in people with serious liver diseases. […] Esophageal varices form when regular blood flow to the liver is blocked by a clot or scar tissue in the liver. To go around the blockages, blood flows into smaller blood vessels that aren’t designed to carry large volumes of blood. The vessels can leak blood or even burst, causing life-threatening bleeding. […] Esophageal varices sometimes form when blood flow to the liver is blocked. This is most often caused by scar tissue in the liver due to liver disease, also known as cirrhosis of the liver. The blood flow begins to back up. This increases pressure within the large vein, known as the portal vein, that carries blood to the liver. This is known as portal hypertension. […] Portal hypertension forces the blood to seek other pathways through smaller veins, such as those in the lowest part of the esophagus. These thin-walled veins balloon with the added blood. Sometimes they rupture and bleed.

• #25 The Progression of Liver Disease to Liver Cancer – American Liver Foundation

  https://liverfoundation.org/resource-center/videos/the-progression-of-liver-disease-to-liver-cancer/

  Liver cancers are 4th most common cause of cancer-related deaths worldwide and it is the 2nd most lethal cancer. While therapies and survival rate for other types of cancer has dramatically improved over the past decades, prognosis of liver cancer remains unfavorable and deadly. In fact, the death rate in the US has increased by more than 40% within the last two decades. […] Majority of the HCC occurs in patients with underlying liver disease. There are many factors that can contribute, including genetic predisposition, family history, environmental exposure, and age and many others, but the underlying theme is that an HCC typically arises from an already damaged liver. They include viral hepatitis, such as hep B, hep C; alcohol disease, fatty liver disease, and now increasing prevalence of obesity and diabetes which amplify the risk of liver diseases and therefore increases the risk of development of a cancer.

• #26 Assessing Liver Function in Rat Models of Acute Liver Failure Using Single-Photon Emission Computed Tomography and Cytokine Levels | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0323531

  Acute liver failure is a severe consequence of abrupt hepatocyte injury from diverse causes. It has a rapid onset that can evolve rapidly within days or weeks to a lethal outcome. The most prevalent causes of acute liver failure are ischemia, drug-induced liver injury, hepatitis B virus, and autoimmunity. The pathology of acute liver failure often shows widespread hepatic necrosis and apoptosis. The clinical manifestations include progressive jaundice, hepatic encephalopathy, and disturbed coagulation. Acute liver failure has a mortality rate as high as 80%. The most common causes of death in patients with acute liver failure are cerebral edema, sepsis, and multisystem organ failure. The prognosis of acute liver failure is poor. Therefore, it is of paramount importance to evaluate liver function and commence management promptly.

• #27 Epigenetics in liver disease: from biology to therapeutics | Gut

  https://gut.bmj.com/content/65/11/1895

  Knowledge of the fundamental epigenetic mechanisms governing gene expression and cellular phenotype are sufficiently advanced that novel insights into the epigenetic control of chronic liver disease are now emerging. […] The study of epigenetics is, in essence, the investigation of how non-genetic factors act upon the genome to influence gene expression and phenotype. Epigenetics can therefore enable us to interrogate the mechanisms that underlie disease phenotype, and it is hoped to shed new light on the basis for interpatient variability in disease progression. […] By illuminating the epigenetic modifications that are associated with specific pathologies such as cirrhosis or cancer we can better understand the molecular basis for loss of cellular homeostasis in chronic liver disease.

• #28 Epigenetics in liver disease: from biology to therapeutics | Gut

  https://gut.bmj.com/content/65/11/1895

  Hepatic stellate cell (HSC) transdifferentiation, from a vitamin A storing pericyte, to a profibrogenic myofibroblastic phenotype, is a pivotal event in fibrogenesis; it occurs in response to a variety of external stimuli such as inflammation and hepatocellular damage. Transdifferentiation requires triggering and orchestrating epigenome-wide reprogramming to suppress adipogenic differentiation factors, de novo expression of myofibroblast regulating transcription factors, and cell cycle entry. […] Recent studies have provided evidence that DNA methylation is a critical event governing the molecular events underpinning fibrogenesis and disease progression. […] Increased DNA methylation during HSC activation occurs at the phosphatase and tensin homolog tumour suppressor ad Patched 1, correlating with its reduced expression in HSCs. […] The progression of chronic human liver disease represents an increase in fibrotic scar deposition and the out-pacing of liver healing by regeneration. Currently, very little is known about the epigenetic control of liver regeneration.

• #29 Regulatory mechanism of HIF-1α and its role in liver diseases: a narrative review

  https://atm.amegroups.org/article/view/85003/html

  HIF-1 is involved in the occurrence and development of various liver diseases, including alcoholic liver disease (ALD), nonalcoholic fatty liver disease (NAFLD), viral hepatitis, liver fibrosis, drug-induced liver injury and hepatocellular carcinoma (HCC). […] HIF-1 participates in complex signaling pathways, and its expression is regulated in many liver diseases. These results suggest the feasibility and clinical significance of targeting HIF-1 to treat liver diseases. […] Long-term alcohol intake can seriously affect liver function, leading to liver hypoxia, steatosis, and eventually ALD development. […] Recent research has shown that HIF-1 is involved in the pathogenesis of ALD. […] A number of mechanisms support the protective effects of HIF-1. […] According to Shao et al., a lack of intestinal HIF-1 can aggravate ALD by inducing intestinal disorders and barrier dysfunction.

• #30 Regulatory mechanism of HIF-1α and its role in liver diseases: a narrative review

  https://atm.amegroups.org/article/view/85003/html

  In summary, HIF-1 plays a complex but indispensable role in the occurrence and development of ALD, and targeting HIF-1 in the liver may be therapeutic for ALD. […] As mentioned above, HIF-1 plays a very important role in NAFLD, with a mechanism of action that is mainly divided into a protective effect by inhibiting excessive accumulation of liver fat and a damaging effect by promoting liver fibrosis. […] HIF-1 helps to reduce bleeding, aseptic inflammation and early hepatocyte necrosis in the pathogenesis of APAP toxicity. […] HIF-1 is widely involved in the occurrence and development of liver cancer. […] HIF-1 overexpression indicates a poor prognosis for HCC patients. […] HIF-1 promotes the migration and invasion of liver cancer cells through the IL-8/NF-B axis. […] In summary, overexpression of HIF-1 promotes HCC; therefore, HIF-1 inhibitors may be used to treat liver cancer. […] Overall, HIF-1 is widely involved in the occurrence, development and prognosis of various liver diseases, and there is increasing evidence that HIF-1 may be involved in complex signaling pathways to regulate its own expression in a variety of liver disease processes.

• #31 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20241108/HMGB1-as-a-key-mediator-in-liver-disease-pathogenesis.aspx

  Liver diseases, both acute and chronic, continue to pose significant clinical challenges due to high morbidity and mortality rates. […] HMGB1 is released from injured or necrotic liver cells and triggers inflammatory responses. Its circulating levels have been associated with disease severity in liver conditions, marking it as a promising biomarker and therapeutic target. […] HMGB1’s interactions with its primary receptors, RAGE and TLR4, are essential to its role in liver disease. Upon binding, these receptors initiate pro-inflammatory signaling pathways such as the NF-B and mitogen-activated protein kinases (MAPK) cascades, exacerbating liver inflammation and injury. […] Importantly, the HMGB1-RAGE axis also plays a role in hepatocellular carcinoma (HCC), influencing tumor proliferation, immune evasion, and metastasis.

• #32 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20241108/HMGB1-as-a-key-mediator-in-liver-disease-pathogenesis.aspx

  In acute liver diseases like APAP-induced liver injury, HMGB1 serves as a key mediator of immune responses, promoting the recruitment of neutrophils and macrophages, which exacerbate liver damage. […] In chronic liver diseases like NAFLD and ALD, HMGB1 plays dual roles depending on its cellular localization. Extracellular HMGB1 promotes inflammatory pathways that accelerate the progression from simple steatosis to more severe forms like nonalcoholic steatohepatitis (NASH). […] Additionally, in liver fibrosis, HMGB1 activates hepatic stellate cells (HSCs), contributing to the fibrotic response, while its modulation of immune responses through macrophage polarization further exacerbates fibrosis. […] Given HMGB1’s critical involvement in liver disease pathogenesis, therapeutic strategies aimed at modulating its release, function, or receptor interactions have gained interest. […] HMGB1 is an integral player in liver disease, influencing both inflammatory and fibrotic pathways. Its roles in acute liver injury, chronic conditions, and liver cancer make it a valuable diagnostic and therapeutic target.

• #33 Human gut fungus reverses liver disease in mice

  https://medicalxpress.com/news/2025-05-human-gut-fungus-reverses-liver.html

  Researchers at Peking University have discovered that a filamentous gut fungus, Fusarium foetens, can reverse metabolic dysfunction–associated steatohepatitis (MASH) in mice. […] Metabolic dysfunction–associated fatty liver disease (MAFLD) is the most common chronic liver disease worldwide and includes progressive forms such as MASH. […] Gut microbiota is associated with the progression of MASH, yet research has focused largely on bacterial communities. […] In the study, „A symbiotic filamentous gut fungus ameliorates MASH via a secondary metabolite–CerS6–ceramide axis,” published in Science, researchers conducted an experimental investigation to determine whether a gut-resident filamentous fungus influences the progression of MASH. […] Genetic, biochemical, and mouse model experiments identified Fusarium foetens as a gut-adapted symbiotic fungus capable of stably colonizing the colon under anaerobic conditions.

• #34 Human gut fungus reverses liver disease in mice

  https://medicalxpress.com/news/2025-05-human-gut-fungus-reverses-liver.html

  Fusarium foetens reversed features of MASH in mouse models fed a choline-deficient, amino acid-defined, high-fat diet. […] Researchers discovered that Fusarium foetens produces a secondary metabolite, FF-C1, which binds directly and noncompetitively to ceramide synthase 6 (CerS6), an enzyme in the ceramide biosynthetic pathway. […] The results support a mechanistic function of a Fusarium foetens metabolite in modifying host lipid metabolism to halt progression of fatty liver disease, while the findings further suggest that intestinal fungi can occupy a symbiotic role in host metabolic regulation. […] Additional investigation is required to identify other fungal species that produce bioactive compounds and to determine whether metabolites derived from Fusarium foetens can be developed as therapeutic agents for human metabolic disease.

• #35 Multiple organs involved in the pathogenesis of non-alcoholic fatty liver disease | Cell & Bioscience | Full Text

  https://cellandbioscience.biomedcentral.com/articles/10.1186/s13578-020-00507-y

  NAFLD is a rising health problem worldwide and related medical burden is also increasing at an alarming rate. The pathogenesis of NAFLD (or MAFLD) is complex and evidently involves multiple organs and diverse mechanisms. The adipose tissue not only contributes fatty acids to facilitate hepatic steatosis but also produces hormones and cytokines to influence proinflammatory pathways. The gut directly takes charge of energy absorption and it communicates with brain to modulate food intake. Gut microbiota has become a hot topic recently as it participates in NAFLD pathogenesis via the gut-liver axis. Altered gut permeability also exposes liver to bacterial components and further triggers immune responses. The central nerve system integrates hormonal and neurol signals to control energy balance, which when impaired leads to obesity and NAFLD. Finally, in the liver, key mechanisms include lipotoxicity, IR, ROS production, ER stress, apoptosis, inflammation, autophagy, etc.

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