Materiały źródłowe

• #1 Non-Alcoholic Fatty Liver Disease (NAFLD) Pathogenesis and Natural Products for Prevention and Treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9779435/

  Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease, affecting approximately one-quarter of the global population, and has become a world public health issue. NAFLD is a clinicopathological syndrome characterized by hepatic steatosis, excluding ethanol and other definite liver damage factors. Recent studies have shown that the development of NAFLD is associated with lipid accumulation, oxidative stress, endoplasmic reticulum stress, and lipotoxicity. […] The pathogenesis of NAFLD is unknown, and this has become a hindrance to the treatment of NAFLD. Early studies suggest that IR and hepatic steatosis due to excess fatty acids are the first-hit, whereas hepatocytes eventually undergo damage, inflammation, fibrosis and other pathological changes due to oxidative stress and lipid peroxidation to form the second-hit. Today, it is widely accepted that the multiple-hit theory is based on the second-hit theory, which includes various factors such as oxidative stress, endoplasmic reticulum (ER) stress and lipotoxicity. This theory also provides a more accurate explanation for the pathogenesis of NAFLD. […] The development of NAFLD is mostly associated with lipid accumulation, oxidative stress, ER stress and lipotoxicity.

• #1 Non-Alcoholic Fatty Liver Disease: From Pathogenesis to Clinical Impact

  https://www.mdpi.com/2227-9717/9/1/135

  Non-Alcoholic Fatty Liver Disease (NAFLD) is caused by the accumulation of fat in over 5% of hepatocytes in the absence of alcohol consumption. NAFLD is considered the hepatic manifestation of metabolic syndrome (MS). […] The pathophysiologic basis of MS, i.e., insulin resistance (IR), also plays a crucial role in NAFLD pathogenesis too, which has led to the consideration of a more appropriate term—MAFLD (metabolic associated fatty liver disease)—to replace NAFLD. […] The aim of this review is to summarize the pathophysiological mechanisms of NAFLD development and its close link with insulin resistance. […] Historically, NAFLD and its progression towards NASH have been attributed to the so-called “two-hits hypothesis.” However, most recent evidence has suggested more complex mechanisms, named as the “multiple parallel hits hypothesis” theory, which involves different elements acting together, rather than in series. According to this theory, IR, genetic and epigenetic factors, mitochondrial dysfunction, endoplasmic reticulum stress, microbiota, chronic low-grade inflammation, and dysfunction of adipose tissue all represent synchronic causes of both NAFLD development and progression.

• #1 Non-Alcoholic Fatty Liver Disease: From Pathogenesis to Clinical Impact

  https://www.mdpi.com/2227-9717/9/1/135

  IR plays a key role in the development of NAFLD, as it causes an increase in hepatic lipogenesis and an inhibition of adipose tissue lipolysis, with a subsequent elevated flow of fatty acids in the liver. […] The hepatic accumulation of triglycerides does not represent itself as a hepatotoxic event, rather as a defense mechanism able to balance the excess FFAs in the plasma. However, other bioactive intermediates, such as ceramides and diacylglycerol (DAG), can induce lipotoxicity, resulting in inflammation, necrosis, and liver fibrosis. NAFLD progresses to NASH when the mechanisms protecting hepatocytes from lipotoxicity are depleted. […] The increase in the mass of visceral adipose tissue also determines, besides the imbalance of adipokine levels, an increase in free fatty acids (FFA) levels. In turn, an excess of FFA is able to determine IR through the inhibition of the post-receptor insulin signal.

• #1 KEGG PATHWAY: map04932

  https://www.genome.jp/dbget-bin/www_bget?map04932

  Non-alcoholic fatty liver disease (NAFLD) represents a spectrum ranging from simple steatosis to more severe steatohepatitis with hepatic inflammation and fibrosis, known as nonalcoholic steatohepatitis (NASH). […] The main cause is the induction of insulin resistance, which leads to a defect in insulin suppression of free fatty acids (FAAs) disposal. […] In addition, two transcription factors, SREBP-1c and PPAR-alpha, activate key enzymes of lipogenesis and increase the synthesis of FAAs in liver. […] The production of reactive oxygen species (ROS) is enhanced due to oxidation stress through mitochondrial beta-oxidation of fatty acids and endoplasmic reticulum (ER) stress, leading to lipid peroxidation. […] The lipid peroxidation can further cause the production of cytokines (Fas ligand, TNF-alpha, IL-8 and TGF), promoting cell death, inflammation and fibrosis. […] The activation of JNK, which is induced by ER stress, TNF-alpha and FAAs, is also associated with NAFLD progression. […] Increased JNK promotes cytokine production and initiation of HCC.

• #1 Non-Alcoholic Fatty Liver Disease: From Pathogenesis to Clinical Impact

  https://www.mdpi.com/2227-9717/9/1/135

  The relationship between IR and NAFLD seems bidirectional. […] The complexity of the insulin metabolic pathway explains why several interferences may affect its biochemical signal. […] The increase in plasma circulating triglycerides also determines an elevated synthesis of plasminogen activator inhibitor-1 (PAI-1) by endothelial cells, supporting the subsequent endothelial dysfunction and the clinical development of arterial hypertension. […] Therefore, an extremely positive caloric balance due to an unhealthy lifestyle causes IR by the increase in visceral adipose tissue and the consequent release of FFA, TNF-α, and adipokines. […] The role of diet, intestinal microbiota, genetic and epigenetic factors, low-degree chronic systemic inflammation, mitochondrial dysfunction, and endoplasmic reticulum stress on NAFLD have been addressed.

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

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

  Twin studies have shown a roughly 50% genetic contribution to hepatic fat content and hepatic fibrosis. […] Genetic variations in hepatic lipid metabolism and insulin signaling have been demonstrated to contribute to development and progression of NAFLD. […] Insulin resistance correlates strongly with the development of nonalcoholic hepatic steatosis and causes profound changes to normal systemic lipid metabolism. […] The development of insulin resistance occurs chiefly in muscle and adipose tissue, whereas hepatic tissue remains largely spared. […] Therapies focused on increasing insulin sensitivity such as rosiglitazone, pioglitazone and liraglutide show promise as potential treatments for NAFLD. […] How the buildup of lipids within the liver leads to the hepatocellular injury seen in nonalcoholic steatohepatitis remains a matter of debate.

• #1

  https://link.springer.com/article/10.1007/s00018-018-2860-6

  The disruption of one or more of these pathways may precipitate the retention of fat within the liver and the subsequent development of NAFLD. Hepatic fat accumulation results from an imbalance between lipid acquisition and lipid disposal, which are regulated through four major pathways: uptake of circulating lipids, de novo lipogenesis (DNL), fatty acid oxidation (FAO), and export of lipids in very low-density lipoproteins (VLDL). […] While the role of hepatic caveolins is still unclear, CD36, FATP2 and -5 mediates increased uptake of circulating lipids in NAFLD. Initially, FABP1 is increased, but levels may decline with disease progression, potentially limiting the mobility of fatty acids and sustaining steatosis. […] Enhanced SREBP1c-mediated de novo lipogenesis is a key feature of NAFLD contributing significantly to the accumulation of lipids.

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

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

  Patients with NASH have been shown to have significant mitochondrial structural abnormalities within their hepatocytes. […] 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. […] Increased intestinal permeability allows endotoxins produced by intestinal bacteria to enter portal circulation and activate TLR-4 signaling in Kupffer cells, leading to downstream increases in proinflammatory cytokines.

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

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

  It is essential to understand the processes that lead to NAFLD and NASH development. […] The initial theory for the pathophysiology of NAFLD was based on two hypotheses. […] The FFA can also promote hepatic lipid accumulation either through -oxidation or esterified with glycerol to form triglycerides. […] 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.

• #1 Nonalcoholic fatty liver disease and type 2 diabetes: pathophysiological mechanisms shared between the two faces of the same coin

  https://www.explorationpub.com/Journals/em/Article/100119

  The accumulation of lipids in the liver induces a chronic endoplasmic reticulum stress of the hepatocytes. […] Inflammatory pathways are critically involved in the development of IR. […] The accumulation of lipids in the liver causes activation of NF-kB and the production of downstream cytokines resulting in subacute hepatic inflammation, determining both hepatic and systemic IR. […] The close association between NAFLD and T2DM is evident and surprisingly it is their bidirectionality. […] NAFLD contributes onset to the development of IR in T2DM. […] Therefore, a diagnosis of hepatic steatosis could be a risk factor for the onset of T2DM, assuming that NAFLD may anticipate the diagnosis of T2DM. […] In conclusion, the relationship between NAFLD and T2DM is not only epidemiological, as evident especially in the context of MS, but above all pathophysiological.

• #1 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. […] Significant hepatocyte injury leads to cell injury and inflammation, subsequently bringing Kupffer cells and other immune cells to the battlefield. […] Immune and apoptotic pathway activation results in cell death, which further drives fibrosis development over time. […] Evidence suggests that ER stress is among the most important factors for NAFLD pathogenesis. […] The ER, an intracellular organelle, is sensitive to lipotoxicity. Dysregulation of ER function is represented by disturbed unfolded protein response (UPR), an adaptively orchestrated arrest of protein synthesis, which can further perpetuate ER stress. […] Activation of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome by LPS from gut microbiota via TLR4 and TLR9 was reported necessary for NASH development since it led to the early onset of steatohepatitis.

• #1 NASH Pathophysiology – PanNASH

  https://pannash.org/pathophysiology/

  Oxidative stress and particularly alterations in mitochondrial function are thought to be a starting point of the hepatic and extrahepatic damage in NAFLD and contribute to the generation of reactive oxygen species (ROS). […] Liver inflammation in NAFLD can be triggered outside the liver such as in adipose tissue and the gut as well as inside the liver. Increased visceral adipose tissue is associated with increased infiltration of inflammatory macrophages, which triggers insulin resistance and inflammation in the adipose tissue and leads to a disturbed adipokine profile, namely high leptin and tumour necrosis factor (TNF) levels and low adiponectin levels. […] Typically, NASH is associated with some degree of hepatic fibrosis, and a small fraction of patients will develop progressive fibrosis and cirrhosis (estimated at 2% of American adults) with some further progressing to HCC.

• #1 Molecular mechanisms of metabolic disease-associated hepatic inflammation in non-alcoholic fatty liver disease and non-alcoholic steatohepatitis

  https://www.explorationpub.com/Journals/edd/Article/100529

  Liver inflammation promotes the progression of hepatic steatosis to NASH and liver fibrosis. […] Both innate and adaptive immune cells are involved in liver inflammation during NAFLD progression, including monocytes, macrophages, neutrophils, myeloid-derived suppressor cells (MDSCs), natural killer (NK) cells, natural killer T (NKT) cells, and B and T lymphocytes. […] Pro-inflammatory cytokines and growth factors secreted from activated immune cells can promote the progression of NAFLD/NASH, such as interferon- (IFN-), interleukin (IL)-1, and granulocyte-macrophage colony-stimulating factor (GM-CSF). […] Abnormal hepatic lipid accumulation, inflammation, and fibrosis, as well as the subsequent cell death, promote the progression of NAFLD to NASH and advanced liver disease, including cirrhosis and HCC.

• #1 Mechanisms of progression in Non-alcoholic fatty liver disease

  https://www.oatext.com/mechanisms-of-progression-in-non-alcoholic-fatty-liver-disease.php

  Inflammatory cytokines are crucial to the development of steatohepatitis. The current literature cites several specific cytokines that have a role, including TNF-a, IL-6, IL-1, IL-17, and IL-18. JNK-1 is a kinase involved in signaling cascade for apoptosis and inflammatory response. In the presence of excess adipose tissue and insulin resistance, activation of the JNK-1 pathway increases the circulating levels of these inflammatory cytokines. Additionally, fatty infiltration of the liver upregulates TGF. In the setting of inflammation, hepatic stellate cells become activated by TGF and secrete extracellular matrix, ultimately causing liver fibrosis. […] Genetic, environmental and lifestyle factors are likely to have some influence on advancing fatty liver disease. However, these are not yet well studied. Certain genes including patatin-like phospholipase domain-containing 3(PNPLA3), transmembrane 6 superfamily 2 (TM6SF2), and glucokinase regulatory protein (GCKR) have been implicated as predisposing factors in progression of NAFLD to NASH.

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

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

  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. […] Hepatic steatosis in NAFLD is primarily caused by systemic insulin resistance, while NASH is majorly caused by lipotoxicity of accumulating lipids and innate immune system activation. […] Fibrosis is caused by excessive secretion of extracellular matrix (ECM) that is not sufficiently balanced by degradation, leading to a net accumulation. […] Existing evidence points to the involvement of bacterial overgrowth in the pathogenesis of NAFLD and NASH. […] GCs sources from both exogenous and endogenous have been recognized to be implicated in NAFLD development.

• #1 Molecular mechanisms of metabolic disease-associated hepatic inflammation in non-alcoholic fatty liver disease and non-alcoholic steatohepatitis

  https://www.explorationpub.com/Journals/edd/Article/100529

  Overall, systemic metabolic disorders and inflammation contribute to the development and progression of NAFLD. […] Hepatic injury, inflammation, and metabolism dysfunction play important roles in NAFLD development. […] Hepatic DNL contributes to fat accumulation in the fatty liver during the development and progression of NAFLD. […] Hepatocyte apoptosis is often shown in cell or animal models and patients with NAFLD. […] Pyroptosis is a programmed cell death accompanied by the activation of inflammasomes. […] Activated HSCs are the main cells that differentiate into myofibroblasts during liver fibrosis. […] Gut-microbiota-derived components and metabolism can induce the capillarization of LSECs to promote NASH, liver fibrosis, and HCC development. […] The innate immune cells, including monocytes, liver macrophages or resident Kupffer cells (KCs), dendritic cells (DCs), neutrophils, NK cells, and NKT cells, play pivotal roles in liver inflammation during NAFLD and NASH.

• #1 Mechanisms of progression in Non-alcoholic fatty liver disease

  https://www.oatext.com/mechanisms-of-progression-in-non-alcoholic-fatty-liver-disease.php

  Gut microbiome is thought to have some role in the pathogenesis of NAFLD. The precise contribution is unclear, however there are several possible influences. First, the intestinal flora can alter bile acid metabolism, which can affect lipid handling and fatty deposition in the liver. The intestinal flora can also produce metabolites and/or endotoxins, which may be hepatotoxic and provide the second hit in the two-hit model. The microbiome also alters host immunity, which may contribute to inflammation. Intestinal bacteria can release pathogen-associated molecular patterns (PAMPs) for damage-associated molecular patterns (DAMPs), which act on toll-like receptors (TLRs) to promote inflammatory response. […] FFAs also interact with sonic hedgehog ligand (SHH), which plays a key role in hepatic regeneration by recruiting inflammatory mediators to the site to clear debris from damaged cells. SHH is released by ballooned degenerated hepatocytes as signal for cellular regeneration. With fatty infiltration and hepatocyte damage, SHH is upregulated and activates hepatic stellate cells, sinusoidal endothelial cells, and other inflammatory cells. These cells, in turn, release pro-inflammatory cytokines, and other fibrogenic mediators, which contribute to inflammation and fibrosis.

• #1 Pathogenesis of non-alcoholic fatty liver disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2810391/

  In obesity and IR there is an increased influx of FFA to the liver. These FFA either undergo -oxidation or are esterified with glycerol to form triglycerides, leading to hepatic fat accumulation. […] There is now substantial evidence that FFA can directly cause toxicity by increasing oxidative stress and by activation of inflammatory pathways, therefore hepatic triglyceride accumulation may be a protective mechanism by preventing the toxic effects of unesterified FFA. […] In the great majority of patients NAFLD develops in association with features of IR and the metabolic syndrome. […] The presence of fibrosis predicts both disease progression and liver-related complications over a subsequent 10-year period. […] NASH also carries an increased risk of hepatocellular carcinoma (HCC) and thus the observation of increased incidence of HCC in type 2 diabetics is likely to be due to their high prevalence of NASH.

• #1 Molecular mechanisms of metabolic disease-associated hepatic inflammation in non-alcoholic fatty liver disease and non-alcoholic steatohepatitis

  https://www.explorationpub.com/Journals/edd/Article/100529

  Given the important roles of liver inflammation in liver diseases, treatment with anti-inflammatory drugs, either alone or in combination with metabolic signaling pathway regulators, is a potent strategy to prevent NAFLD progression. […] This review focuses on the effects of metabolic disease-induced extrahepatic inflammation, liver inflammation, and the cellular and molecular mechanisms of liver metabolism on the development and progression of NAFLD and NASH, as well as the associated treatments. […] Extrahepatic inflammatory factors can contribute to the onset and progression of NAFLD, such as adipokines and gut hormones. […] For example, pro-inflammatory cytokines secreted from adipose tissues and intestinal epithelium cells, such as IL-1 and tumor necrosis factor (TNF)- can transfer into the liver to induce immune cell activation.

• #1 Molecular mechanisms of metabolic disease-associated hepatic inflammation in non-alcoholic fatty liver disease and non-alcoholic steatohepatitis

  https://www.explorationpub.com/Journals/edd/Article/100529

  Overall, adipose tissue metabolic disorder and inflammation play important roles in extrahepatic and hepatic inflammation. […] Insulin resistance can directly contribute to NAFLD by increasing DNL and indirectly suppress lipolysis by increasing the delivery of FFAs to the liver. […] Inflammation plays a pivotal role in the development and progression of CKD. […] A higher prevalence of CKD has been shown in patients with NAFLD compared to that in subjects without NAFLD. […] Pro-inflammatory cytokines such as IL-1, IL-17, and TNF are commonly increased in the pathogenesis of CVD and atherosclerosis. […] The gut-liver axis is defined as the bidirectional relationship between the gut, along with gut microbiota, with the liver. […] Dysbiosis of gut microbiota and increased intestinal permeability result in NAFLD progression by increasing the transportation of gut-microbiota-derived components and metabolites into the liver.

• #1 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 central nerve system plays a predominating role in energy regulation as neuronal networks and nuclei in certain brain regions crosstalk and integrate peripheral signals like plasma nutrients and key metabolic hormones to coordinate adaptive changes in food intake and energy expenditure. […] 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.

• #1 NASH Pathophysiology – PanNASH

  https://pannash.org/pathophysiology/

  An understanding of the pathogenesis and natural course of NAFL and NASH is essential. […] Non-alcoholic steatohepatitis (NASH), resulting from a combination of adipose tissue insulin resistance, adipocytokine imbalance and systemic inflammation, is currently a major worldwide cause of chronic liver disease, contributing to cirrhotic morbidity, hepatocellular carcinoma and liver transplantation, and worsening cardiovascular disease and metabolic dysfunction. […] Several genetic mutations have been noted to be associated with NASH and have added to the implication of lipid and glucose metabolism involvement in NAFLD progression. The best-studied polymorphisms are mutations in genes encoding patatin-like phospholipase domain-containing protein 3 (PNPLA3), the prevalence of which differs among populations and appears to parallel that of NASH; however, the mechanism by which the effects are produced is incompletely understood.

• #1 Non-alcoholic fatty liver disease: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/non-alcoholic-fatty-liver-disease/

  The PNPLA3 gene variation associated with NAFLD is thought to lead to increased production and decreased breakdown of fats in the liver. […] An increased risk of developing NAFLD can be passed through generations in families, but the inheritance pattern is unknown. Variations in several genes as well as lifestyle and environmental factors contribute to the risk of developing this complex disorder.

• #1 NASH Pathophysiology – PanNASH

  https://pannash.org/pathophysiology/

  Lipotoxicity (a term coined by Unger) is caused by toxic precursors of triglycerides or their metabolites and is thought to play a central role in the pathogenesis of NASH. According to the substrate-overload liver injury model of NASH pathogenesis, the livers capacity to handle the primary metabolic energy substrates, carbohydrates and fatty acids is overwhelmed, leading to the accumulation of toxic lipid species. NASH has been described as the sum of injury and repair responses triggered by lipotoxicity. […] Hepatic inflammation is an important component of the process, but it is unclear whether it is a primary cause or consequence (or both) of hepatocyte injury and death. […] The inflammatory and immune systems, namely macrophages, are involved as well. There is a close relationship between insulin-resistant adipocytes, dysregulated immunity and steatohepatitis. Activated adipose tissue macrophages are important in adipose tissue FFA release, insulin resistance and subsequent liver fat deposition.

• #1 Cardiovascular Risk in NAFLD | ECR Journal

  https://www.ecrjournal.com/articles/management-cardiovascular-risk-non-alcoholic-fatty-liver-disease-setting?language_content_entity=en

  Non-alcoholic fatty liver disease (NAFLD) is an overlooked and undetected pathology, which affects more than 32% of adults worldwide. […] NAFLD has traditionally been interpreted as a liver disease with a high risk of liver-related complications, NAFLD is an underappreciated and independent risk factor for atherosclerotic cardiovascular disease, which is the principal cause of death in patients with NAFLD. […] The pathophysiology behind the association of NALFD with other CVDs remains incompletely understood. There are different theories. The most accepted theory implicates insulin resistance as the key mechanism leading to hepatic steatosis, and perhaps also to steatohepatitis. […] Some of the mechanisms by which NAFLD increases CVD risk include systemic inflammation, endothelial dysfunction, hepatic insulin resistance, oxidative stress and altered lipid metabolism.

• #1 Cardiovascular Risk in NAFLD | ECR Journal

  https://www.ecrjournal.com/articles/management-cardiovascular-risk-non-alcoholic-fatty-liver-disease-setting?language_content_entity=en

  NAFLD, especially in its necroinflammatory form (non-alcoholic steatohepatitis; NASH), may also cause atherogenic dyslipidaemia. […] Inflammation is also crucial in the pathogenesis of NAFLD. NAFLD is considered to generate chronic sub-clinical inflammation and is associated with many markers of inflammation. […] The underlying mechanisms linking NAFLD to CVD are very complex and involve several different pathways simultaneously. […] The available evidence not only demonstrates the strong association between NALFD and CVD, but also supports the view that NAFLD may increase the risk of incident CV events. […] Strong evidence links NAFLD to objectively assessed subclinical atherosclerosis, including coronary artery calcium score in adults and adolescents, as well as to an increased prevalence of clinically manifest CVD both in the general population and in different patient groups.

• #1 Pathogenesis of non-alcoholic fatty liver disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2810391/

  The traditional 2-hit hypothesis of NAFLD pathogenesis has been modified several times; in most patients however NAFLD does appear to begin with lipid accumulation, or steatosis, which is in turn driven by obesity and IR. Progression to steatohepatitis and fibrosis depends on additional factors such as FFAs, inflammatory cytokines and adipokines, oxidative stress and mitochondrial dysfunction in a complex interplay with genetic predisposition.

• #1 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

  Hence, its objective to regard liver fibrosis as a well-orchestrated advantageous response towards hepatic injury, while the ongoing insults against liver should be to blame for disease progression to cirrhosis or hepatocellular carcinoma (HCC). […] 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. […] 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.

• #2 Pathogenesis of non-alcoholic fatty liver disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2810391/

  Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of disease ranging from hepatocellular steatosis through steatohepatitis to fibrosis and irreversible cirrhosis. […] The metabolic syndrome comprises a cluster of clinical and biochemical features, namely IR, glucose intolerance or diabetes, central obesity, hypertension and dyslipidaemia and is associated with significant cardiovascular morbidity and mortality. […] Although the pathogenesis of NAFLD/NASH is not yet fully understood, much progress has been made in recent years in elucidating the mechanisms of progression from steatosis to more advanced liver inflammation and fibrosis. […] Initial theories for the pathogenesis of NASH were based on a 2-hit hypothesis. The first hit, hepatic triglyceride accumulation, or steatosis, increases susceptibility of the liver to injury mediated by second hits, such as inflammatory cytokines/adipokines, mitochondrial dysfunction and oxidative stress, which in turn lead to steatohepatitis and/or fibrosis.

• #2 Pathogenesis of non-alcoholic fatty liver disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2810391/

  The traditional 2-hit hypothesis of NAFLD pathogenesis has been modified several times; in most patients however NAFLD does appear to begin with lipid accumulation, or steatosis, which is in turn driven by obesity and IR. Progression to steatohepatitis and fibrosis depends on additional factors such as FFAs, inflammatory cytokines and adipokines, oxidative stress and mitochondrial dysfunction in a complex interplay with genetic predisposition.

• #2 Non-Alcoholic Fatty Liver Disease (NAFLD) Pathogenesis and Natural Products for Prevention and Treatment

  https://www.mdpi.com/1422-0067/23/24/15489

  Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease, affecting approximately one-quarter of the global population, and has become a world public health issue. NAFLD is a clinicopathological syndrome characterized by hepatic steatosis, excluding ethanol and other definite liver damage factors. Recent studies have shown that the development of NAFLD is associated with lipid accumulation, oxidative stress, endoplasmic reticulum stress, and lipotoxicity. […] The pathogenesis of NAFLD is unknown, and this has become a hindrance to the treatment of NAFLD. Early studies suggest that IR and hepatic steatosis due to excess fatty acids are the “first-hit”, whereas hepatocytes eventually undergo damage, inflammation, fibrosis and other pathological changes due to oxidative stress and lipid peroxidation to form the “second-hit”. Today, it is widely accepted that the “multiple-hit” theory is based on the “second-hit” theory, which includes various factors such as oxidative stress, endoplasmic reticulum (ER) stress and lipotoxicity. This theory also provides a more accurate explanation for the pathogenesis of NAFLD. […] The development of NAFLD is mostly associated with lipid accumulation, oxidative stress, ER stress and lipotoxicity.

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

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

  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. […] Hepatic steatosis in NAFLD is primarily caused by systemic insulin resistance, while NASH is majorly caused by lipotoxicity of accumulating lipids and innate immune system activation. […] Fibrosis is caused by excessive secretion of extracellular matrix (ECM) that is not sufficiently balanced by degradation, leading to a net accumulation. […] Existing evidence points to the involvement of bacterial overgrowth in the pathogenesis of NAFLD and NASH. […] GCs sources from both exogenous and endogenous have been recognized to be implicated in NAFLD development.

• #2 Nonalcoholic fatty liver disease and type 2 diabetes: pathophysiological mechanisms shared between the two faces of the same coin

  https://www.explorationpub.com/Journals/em/Article/100119

  The accumulation of lipids in the liver induces a chronic endoplasmic reticulum stress of the hepatocytes. […] Inflammatory pathways are critically involved in the development of IR. […] The accumulation of lipids in the liver causes activation of NF-kB and the production of downstream cytokines resulting in subacute hepatic inflammation, determining both hepatic and systemic IR. […] The close association between NAFLD and T2DM is evident and surprisingly it is their bidirectionality. […] NAFLD contributes onset to the development of IR in T2DM. […] Therefore, a diagnosis of hepatic steatosis could be a risk factor for the onset of T2DM, assuming that NAFLD may anticipate the diagnosis of T2DM. […] In conclusion, the relationship between NAFLD and T2DM is not only epidemiological, as evident especially in the context of MS, but above all pathophysiological.

• #2 Understanding lipotoxicity in NAFLD pathogenesis: is CD36 a key driver? | Cell Death & Disease

  https://www.nature.com/articles/s41419-020-03003-w

  The excessive FFA influx to hepatocytes is the earliest event triggering lipotoxicity and currently it is well known that the fatty acid translocase CD36 plays a key role increasing FFA uptake and its utilisation not only in hepatocytes, but also in KCs and HSCs. […] There is convincing experimental evidence by studying in vitro systems and animal models of NAFLD that CD36 drives hepatosteatosis onset and might contribute to its progression to NASH. […] Clinical studies have reinforced the significance of CD36 in NAFLD pathogenesis in humans as hepatic CD36 content is markedly increased in NAFLD patients and, interestingly, circulating levels of a soluble form of CD36 are abnormally elevated in those patients and positively correlate with the histological grade of hepatic steatosis.

• #2

  https://link.springer.com/article/10.1007/s00018-018-2860-6

  In short, DNL enables the liver to synthesize new fatty acids from acetyl-CoA. […] Increased DNL can cause hepatic steatosis and/or hypertriglyceridemia, but may also induce steatohepatitis, as saturated fatty acids, such as palmitate, can cause inflammation and apoptosis. […] The transcriptional regulation of DNL is mainly orchestrated by two key transcription factors: sterol regulatory element-binding protein 1c (SREBP1c), which is activated by insulin and liver X receptor, and carbohydrate regulatory element-binding protein (ChREBP), which is activated by carbohydrates. […] In NAFLD, hepatic lipid acquisition mediated by increased fatty acid uptake and DNL is enhanced despite the presence of steatosis. Lipid disposal may be increased, but is ultimately incapable of counteracting the growing intrahepatic fat deposition. […] While lipid export is enhanced in early disease stages, it decreases or plateaus with disease severity as hepatocyte metabolism becomes increasingly compromised.

• #2 NASH Pathophysiology – PanNASH

  https://pannash.org/pathophysiology/

  Lipotoxicity (a term coined by Unger) is caused by toxic precursors of triglycerides or their metabolites and is thought to play a central role in the pathogenesis of NASH. According to the substrate-overload liver injury model of NASH pathogenesis, the livers capacity to handle the primary metabolic energy substrates, carbohydrates and fatty acids is overwhelmed, leading to the accumulation of toxic lipid species. NASH has been described as the sum of injury and repair responses triggered by lipotoxicity. […] Hepatic inflammation is an important component of the process, but it is unclear whether it is a primary cause or consequence (or both) of hepatocyte injury and death. […] The inflammatory and immune systems, namely macrophages, are involved as well. There is a close relationship between insulin-resistant adipocytes, dysregulated immunity and steatohepatitis. Activated adipose tissue macrophages are important in adipose tissue FFA release, insulin resistance and subsequent liver fat deposition.

• #2 Oxidative stress in nonalcoholic fatty liver disease: a reappraisal of the role in supporting inflammatory mechanisms in: Redox Experimental Medicine Volume 2022 Issue 1 (2022)

  https://rem.bioscientifica.com/view/journals/rem/2022/1/REM-22-0002.xml

  In the last decade, non-alcoholic fatty liver disease (NAFLD) and particularly its evolution to nonalcoholic steatohepatitis (NASH) have become a leading cause of chronic liver disease and cirrhosis as well as an important risk factor for hepatocellular carcinoma. […] Oxidative stress is a common feature of NAFLD/NASH and plays a key role in the complex of metabolic and cellular derangements that are involved in the development of liver steatosis, as well as in the transition to steatohepatitis. […] This review deals with the contribution of oxidative stress in promoting hepatic inflammation which represents a key factor in NAFLD evolution to liver fibrosis/cirrhosis. […] The involvement of oxidative stress mechanisms in the pathogenesis of NAFLD/NASH stems from the observation that an increase in oxidative stress markers is a common feature in either rodent models of NAFLD/NASH or the human disease.

• #2 Oxidative stress in nonalcoholic fatty liver disease: a reappraisal of the role in supporting inflammatory mechanisms in: Redox Experimental Medicine Volume 2022 Issue 1 (2022)

  https://rem.bioscientifica.com/view/journals/rem/2022/1/REM-22-0002.xml

  The key role played by hepatic inflammation in the progression of NAFLD has led to a great number of studies investigating the contribution of both innate and adaptative immunity. […] The activation of resident Kupffer cells is currently seen as a key element in the onset of hepatic inflammation in NASH. […] As a result of these stimuli, activated Kupffer cells release cytokines, chemokines, eicosanoids, nitric oxide (NO), and ROS. […] The characterization of liver macrophage expanding in either human and rodent NASH using single-cell RNA sequencing has revealed that during NASH progression embryonically derived Kupffer cells are progressively lost and replaced by monocyte-derived macrophages that have a specific phenotype characterized by the expression of the triggering receptor expressed on myeloid cells 2 (TREM-2).

• #2 Non-alcoholic fatty liver disease: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/non-alcoholic-fatty-liver-disease/

  Non-alcoholic fatty liver disease (NAFLD) is a buildup of excessive fat in the liver that can lead to liver damage resembling the damage caused by alcohol abuse, but that occurs in people who do not drink heavily. […] The specific causes of NAFLD are unclear. Genetic variations and environmental factors contribute to the development of this complex disorder. […] Researchers are studying several possible mechanisms. These include inflammation caused by an immune system reaction to the excess fatty tissue in the liver; toxic inflammatory chemicals (cytokines) released by the liver cells or fat cells; self-destruction (apoptosis) of liver cells; and the effect of unstable molecules called free radicals (oxidative stress). […] Studies have identified many genetic changes that may be associated with the development of NAFLD and NASH. Among these is a particular variation in the PNPLA3 gene.

• #2 Cardiovascular Risk in NAFLD | ECR Journal

  https://www.ecrjournal.com/articles/management-cardiovascular-risk-non-alcoholic-fatty-liver-disease-setting?language_content_entity=en

  NAFLD, especially in its necroinflammatory form (non-alcoholic steatohepatitis; NASH), may also cause atherogenic dyslipidaemia. […] Inflammation is also crucial in the pathogenesis of NAFLD. NAFLD is considered to generate chronic sub-clinical inflammation and is associated with many markers of inflammation. […] The underlying mechanisms linking NAFLD to CVD are very complex and involve several different pathways simultaneously. […] The available evidence not only demonstrates the strong association between NALFD and CVD, but also supports the view that NAFLD may increase the risk of incident CV events. […] Strong evidence links NAFLD to objectively assessed subclinical atherosclerosis, including coronary artery calcium score in adults and adolescents, as well as to an increased prevalence of clinically manifest CVD both in the general population and in different patient groups.

• #3 Molecular mechanisms of metabolic disease-associated hepatic inflammation in non-alcoholic fatty liver disease and non-alcoholic steatohepatitis

  https://www.explorationpub.com/Journals/edd/Article/100529

  Non-alcoholic fatty liver disease (NAFLD) is the leading chronic liver disease worldwide, with a progressive form of non-alcoholic steatohepatitis (NASH). It may progress to advanced liver diseases, including liver fibrosis, cirrhosis, and hepatocellular carcinoma. NAFLD/NASH is a comorbidity of many metabolic disorders such as obesity, insulin resistance, type 2 diabetes, cardiovascular disease, and chronic kidney disease. […] These metabolic diseases are often accompanied by systemic or extrahepatic inflammation, which plays an important role in the pathogenesis and treatment of NAFLD or NASH. […] Multiple genetic, epigenetic, and environmental factors are involved in the pathogenesis of NAFLD. […] Dyslipidemia is also often accompanied by liver inflammation and metabolic disorders, such as insulin resistance.

• #3 Pathogenesis of non-alcoholic fatty liver disease in children and adolescence: From “two hit theory” to “multiple hit model”

  https://www.wjgnet.com/1007-9327/full/v24/i27/2974.htm

  Early theories of the pathogenesis of NAFLD and NASH were described in terms of the two hit hypothesis. […] Subsequently, the second hit emerges, which includes inflammatory cytokines, adipokines, mitochondrial dysfunction, and oxidative stress. […] Now, the widely accepted theory is the multiple-hit model, involving more widespread metabolic dysfunction because of the interaction of genetic and environmental factors as well as changes in crosstalk between different organs and tissues, including adipose tissue, the pancreas, gut, and liver. […] However, liver fat accumulation, caused by obesity and insulin resistance, still seem to represent the first hits. […] In summary, hepatocyte damage is an indicator of NASH progression. […] The initial two-hit theory can no longer completely explain the pathogenesis of NAFLD, which involves multiple factors. […] More recently, with the development of technology (especially GWAS), increasing studies have focused on genetic predispositions and found various gene variants that may alter lipid and sugar metabolism in the liver as well as in other tissues such as adipose tissue.

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