Materiały źródłowe

• #1 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 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.

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

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

  Non-alcoholic fatty liver disease (NAFLD) is a growing public health concern in the United States (US). […] To date, the mechanism of progression in NAFLD is not well understood. This review aims to discuss several proposed mechanisms in development of NASH and NASH-related cirrhosis. […] The most widely accepted theory in the pathogenesis of NAFLD is described by a two-hit model. The first hit is infiltration of hepatotoxic free fatty acids (FFAs) in the liver, making it vulnerable to a second hit. Hepatic lipotoxicity results from generation of toxic lipid metabolites from FFAs, such as ceramides, diacylglycerols, lysophosphatidyl choline, and oxidized cholesterol metabolites. […] The second hit can be any number of insults ranging from impaired mitochondrial function, drug toxicity, iron overload, ischemia, disordered adipokine activity, or other inflammatory damage.

• #4 Pathogenesis and Therapeutic Strategies Related to Non-Alcoholic Fatty Liver Disease

  https://www.mdpi.com/1422-0067/23/14/7841

  The “multiple hits hypothesis” is considered to accurately explain NAFLD pathogenesis. According to this view, NAFLD pathogenesis is jointly induced by multiple factors, including insulin resistance, nutritional factors, oxidative stress, inflammatory factors, obesity, type 2 diabetes, hormones, gut microbiota, and epigenetic factors. […] In recent years, some new progress has been reported involving the pathogenesis of NAFLD, including pro-inflammatory diets, gut metabolome, adipose tissue inflammation, genetic factors, etc. […] The activation of the NLPR3 inflammasome has been considered as a vital factor in the progress of NAFLD, especially as a modulator of progression from initial hepatic steatosis to NASH. […] The increased expression of several chemokines, including c-c motif chemokine ligand 2 (ccl2), ccl5, and ccl13, were able to recruit at the macrophages (ATM) and normal T cells and to initiate at inflammation in obese patients.

• #5 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. Fat accumulates within the hepatocytes mainly as triglycerides deriving from the esterification of glycerol and FFAs. 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. This induces necrosis and secondary repair phenomena mediated by hepatic stellate cells, with the deposition of scar collagen tissue, hence the development and progression of fibrosis.

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

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

  NAFLD is a broad-spectrum term used to describe anything from fat accumulation in hepatocytes without inflammation or fibrosis (simple hepatic steatosis) to hepatic steatosis with a necroinflammatory component (steatohepatitis) with or without associated fibrosis. […] The pathogenesis is not fully understood for either disease. […] By contrast, insulin resistance is widely believed to be the main driver of nonalcoholic hepatic steatosis. […] The mechanism behind the transition from nonalcoholic steatosis to steatohepatitis remains a matter of debate with insulin resistance, oxidative injury, hepatic iron, gut hormones, antioxidant deficiency, and host microbiome all suspected to play part of the role. […] 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.

• #7 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.

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

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

  The complexity of the insulin metabolic pathway explains why several interferences may affect its biochemical signal. On the other hand, IR may be mediated by alterations at any level of its biochemical signal cascade. […] 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. […] The relationship between IR and NAFLD seems bidirectional. Indeed, the complex network of events involved in the development of NASH may determine an increase in hepatic IR up-regulating SOCS-3 which, through the interference with IRS-1, determines a reduced insulin signal transmission. Therefore, it seems likely that an improvement in IR degree could help to reduce NAFLD progression and should thus be considered among the main therapeutic targets.

• #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

  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. Inflammatory mechanisms, such as the production of proinflammatory extracellular vesicles and cell death, are activated due to lipid-induced sub-lethal and lethal stress. […] Fibrosis is caused by excessive secretion of extracellular matrix (ECM) that is not sufficiently balanced by degradation, leading to a net accumulation. In the models of toxic, biliary liver disease and NAFLD, hepatic stellate cells (HSC) are the primary source of ECM-producing fibroblasts. […] Existing evidence points to the involvement of bacterial overgrowth in the pathogenesis of NAFLD and NASH. The gut microbiome is implicated in the pathogenesis and progression of NAFLD through the so-called gut-liver axis, investigating that the gut microbiome could be considered a metabolic organ in the host, which can affect human metabolism in health and disease.

• #10

  https://journals.lww.com/hep/fulltext/2019/08000/modulation_of_insulin_resistance_in_nonalcoholic.24.aspx

  Insulin resistance selectively inhibits the hypoglycemic effects of insulin, while allowing de novo lipogenesis to continue, via activation of sterol regulatory element binding protein (SREBP1). […] In NAFLD, there is an increased availability of free fatty acids (FFAs) secondary to increased fatty dietary intake and release from adipose tissue. […] FFAs are converted to triacylglyerols (TAG) via the glycerol 3 phosphate (G3P) pathway. […] Adiponectin is an inhibitor of this pathway, but levels of adiponectin are reduced in patients with NAFLD. […] Diacylglycerol (DAG) and ceramides are metabolites that accumulate in this pathway and can inhibit insulin signaling, via molecules such as protein kinase C (PKC). […] Fatty acyl-CoA is another metabolite in the G3P pathway and serves as an entry point for mitochondrial oxidation.

• #11

  https://journals.lww.com/hep/fulltext/2019/08000/modulation_of_insulin_resistance_in_nonalcoholic.24.aspx

  It is hypothesized that IR is caused by accumulation of lipid metabolites in this pathway, such as ceramides and diacylglycerols (DAGs). […] Animal studies suggest that accumulation of DAG plays a central role in mediating the relationship between steatosis and IR, by activation of PKC. […] Isotopic tracer studies have shown that patients with NAFLD have an increase in de novo lipogenesis compared to those without NAFLD. […] This is a paradoxical finding given that insulin normally promotes lipogenesis, and that downstream from the insulin receptor, the pathway by which insulin modulates glucose levels hypothetically must diverge from the pathway that mediates lipogenesis. […] The ideal medical treatment for NAFLD would improve biochemical and histological features, reduce risk of progression to end-stage liver disease, and simultaneously reduce cardiovascular risk. Thus, modulation of IR will be a mainstay of therapeutic approaches in NAFLD given that it focuses on the upstream pathogenesis of NAFLD, yet improvements in IR do not always correlate with histological improvement. […] NAFLD has a multifactorial pathogenesis; hence, combinatorial approaches targeting different mechanisms may enable synergism of beneficial effects while minimizing risks.

• #12 Understanding mechanisms of the pathogenesis of nonalcoholic fatty liver disease

  https://www.wjgnet.com/1007-9327/full/v16/i18/2223.htm

  Increased production of ROS and lipid peroxidation of hepatocyte membranes and organelles promote necroinflammation, satellite cell activation and fibrosis in the liver. […] Insulin resistance and peripheral lipolysis cause an increased FFA pool in the circulation. […] This pool is one of the major sources of hepatic TGs. […] FFAs play a major role in the transition from simple steatosis to NASH. […] Oxidative stress is one of the most popular proposed mechanisms of hepatocellular injury in NASH in both animal experiments and human trials. […] Hepatocyte mitochondria are the main site of -oxidation of FFAs and adenosine triphosphate (ATP) production is one of the crucial issues in the understanding of NASH pathogenesis. […] Increased oxidative stress and lipid peroxidation products are integral components of the pathway progressing to NASH from fatty liver.

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

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

  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. […] 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.

• #14

  https://journals.lww.com/hep/fulltext/2019/08000/modulation_of_insulin_resistance_in_nonalcoholic.24.aspx

  In NAFLD, there is an increase in mitochondrial oxidation in response to the increased lipogenesis, but there is concomitant mitochondrial dysfunction, resulting in oxidative stress, which can inhibit insulin signaling via activation of inhibitor of nuclear factor kappaB (IB) kinase subunit beta (IKK) and c-Jun N-terminal kinase (JNK). […] Inflammatory cytokines, such as those produced by adipocytes and macrophages can also activate (IKK), JNK and additionally suppressor of cytokine signaling (SOCS), which can phosphorylate IRS1 and IRS2 to inhibit insulin signaling. […] The net effects of the above processes are an increase in inflammation, a reduction in glycogen synthesis, an increase in lipogenesis and an increase in blood insulin and blood glucose levels. […] Patients with NAFLD have increased levels of serum free fatty acids (FFAs) compared to those without NAFLD, attributed to a failure of insulin-mediated suppression of lipolysis, allowing release of excess FFAs into the bloodstream.

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

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

  The influences of oxidative stress and mitochondrial dysfunction in NAFLD and NASH are well-recognized. Within the normal liver, -oxidation occurs in the mitochondria but in the setting of NAFLD, this process can become overwhelmed due to elevated FFA load, leading to the generation of ROS. ROS stimulate oxidative stress with a progressive activation of mitochondrial damage and inflammatory pathways. […] Endoplasmic reticulum (ER) stress is another pathway associated with the pathophysiology of NAFLD and NASH. Unfolded proteins can accumulate within the ER, due to the increased protein synthesis input, the dysfunctional ER or a lack of ATP, which can activate the so-called unfolded protein response (UPR), an adaptive response designed to alleviate ER stress. […] 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. Hepatocytes store fat mostly in the form of triglycerides generated by the esterification of glycerol and FFAs.

• #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. […] 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. […] A recent publication reported that ablation of p38 gene in the liver could increase simple steatosis but attenuate oxidative stress-induced injury and fibrosis during NAFLD.

• #17 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.

• #18 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

  Currently, the pathophysiological mechanisms underlying the close relationship between NAFLD and T2DM are multiple, complex and only partially clarified. […] Insulin resistance (IR) appears to be the main physiopathological link between NAFLD and T2DM. […] In fact, it has been known for years how MS may underpin both NAFLD and T2DM. […] The strong association between IR, hyperinsulinemia, glucose intolerance, reduced high density lipoprotein cholesterol levels and hypertension has been well-known since the end of 80s. […] The accumulation of lipids in the liver induces a chronic endoplasmic reticulum stress of the hepatocytes. […] 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.

• #19 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). Recently, an expert consensus suggested as more appropriate the term MAFLD (metabolic-associated fatty liver disease). Insulin resistance (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. Beyond the imbalance of adipokine levels, the increase in the mass of visceral adipose tissue also determines an increase in free fatty acid (FFA) levels. In turn, an excess of FFA is able to determine IR through the inhibition of the post-receptor insulin signal. Adipocytes secrete chemokines, which are able to enroll macrophages inside the adipose tissue, responsible, in turn, for the increased levels of TNF-α. The latter, as well as resistin and other pro-inflammatory cytokines such as IL-6, enhances insulin resistance and correlates with endothelial dysfunction and an increased cardiovascular (CV) risk. In this review, 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. Finally, the clinical impact of NAFLD on cardiovascular and renal outcomes, and its direct link with type 2 diabetes have been discussed.

• #20 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 detrimental and protective roles of p38 in different disease stages remind us that NAFLD therapies targeting ASK1-p38 pathway have to proceed with caution. […] Finally, autophagy has also been suggested participating in NAFLD. […] Loss of autophagic modulation against cell death leads to hepatic steatosis and the shift from NAFLD to NASH. […] The energy expenditure hormone leptin is mainly secreted by visceral adipocytes and its involved in a range of energy modulating activities including hunger, food energy utilization, physical exercise, thermogenesis, and fat mass regulation. […] Leptin could also upregulate the expression of transforming growth factor (TGF)- in Kupffer cells and sinusoidal endothelial cells, which contributes to liver fibrogenesis. […] Another major adipokine is adiponectin, which is an adipocyte-derived anti-inflammatory mediator eliciting AMP-activated protein kinase (AMPK) signaling.

• #21 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

  In NASH patients, circulating adiponectin levels were remarked diminished, and the downregulation of hepatic adiponectin could be reserved by weight loss. […] The association between gut permeability and NAFLD is highlighted by the finding in a high-fat dietary model of NAFLD that increased circulating Lipopolysaccharide (LPS) levels correlated with worsened steatohepatitis, as measured by the NAFLD Activity Score and liver enzyme levels. […] Increased TLR ligands could be detected in the portal system in the presence of gut dysbiosis, which contributes to the activation of TLR4 on Kupfer cells and stellate cells and subsequent stimulation of pro-inflammatory and profibrotic pathways. […] 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.

• #22 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.

• #23 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 pathophysiological mechanisms underlying the close relationship between nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) are multiple, complex and only partially known. […] Subjects with NAFLD and T2DM have established insulin resistance (IR), which exacerbates the two comorbidities. […] IR worsens NAFLD by increasing the accumulation of free fatty acids (FFAs) in the liver. […] Genome-wide association studies have identified genetic variants associated with NAFLD severity, but unrelated to IR. […] The close association between NAFLD and T2DM is bidirectional, as T2DM may trigger both NAFLD onset and its progression, but NAFLD itself may contribute to the development of IR and T2DM. […] Therefore, NAFLD and T2DM cannot be dissociated, due to the double thread that binds them.

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

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

  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. […] Although there are many proposed mechanisms contributing to the advancement of NAFLD, further research is needed to understand how each of the mechanisms described above fit into the overall pathogenesis.

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

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

  GCs sources from both exogenous and endogenous have been recognized to be implicated in NAFLD development. Individuals with Cushings syndrome, who have elevated GCs levels are associated with characteristic metabolic phenotype, including IR, central obesity, and DM, and many of these patients will have hepatic steatosis. […] Innate immune cells play a crucial role in the pathogenesis of NAFLD. Although the innate immune system is activated and proinflammatory monocytes are recruited into the liver in NASH, the precise signals that result from this are still poorly understood. […] Identification of genetic factors to determine the risk of disease progression may assist to evaluate individuals who may have associated morbidity. Various genes associated with NAFLD have been investigated but the most frequent variant; p.I148M of the enzyme adiponectin gene is one of the major genetic determinants of steatosis and steatohepatitis, fibrosis, cirrhosis, and hepatocellular cancer.

• #26 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 hypothalamic arcuate nucleus (ARC) is considered as the most important central sensor for signals in circulation and cerebrospinal fluid because it is anatomically adjacent to the median eminence and the third ventricle. […] Both the liver and the gut are rich in vagal afferent fibers which transmit local information to the brain stem, another key area involved in the central regulation of energy balance. […] The AMPK-malonylCoA-CPT1 axis has already been targeted for the therapy of NASH. […] Interestingly, gut dysbiosis and relevant endotoxemia are considered partially contributing to the dysregulation of gut-brain vagal communication and subsequent outcomes such as obesity and NAFLD.

• #27 Fatty Liver: A Link to Cardiovascular Disease – Its Natural History, Pathogenesis, and Treatment | Methodist DeBakey Cardiovascular J

  https://journal.houstonmethodist.org/articles/10.14797/mdcj-8-3-21

  Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent liver disease in western society and is increasing in parallel with the worldwide epidemic of obesity. […] Increasingly, NAFLD and its more sinister form, steatohepatitis, have been linked to the increased incidence of cardiovascular disease (CVD) worldwide, independent of the metabolic syndrome. […] NAFLD can progress to cirrhosis and hepatocellular carcinoma.

• #28 NASH Pathophysiology – PanNASH

  https://pannash.org/pathophysiology/

  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. […] 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. […] 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.

• #29 Nonalcoholic fatty liver disease: from pathogenesis to patient care | Nature Reviews Endocrinology

  https://www.nature.com/articles/ncpendmet0505

  Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in Western countries. […] Insulin resistance is one of the key elements of the pathogenesis of NAFLD. […] Liver biopsy is the only way to assess the histologic features of necrotic inflammation and fibrosis that define nonalcoholic steatohepatitis and to determine its probable prognosis. […] The prognosis is good for pure steatosis, whereas the presence of necrotic inflammation is associated with a significant risk of progression to cirrhosis and, possibly, hepatocellular carcinoma. […] NAFLD can progress to cirrhosis and hepatocellular carcinoma.

• #30 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.

• #31 Fatty Liver: Overview, Etiology, Epidemiology

  https://emedicine.medscape.com/article/175472-overview

  NAFLD includes NAFL (nonalcoholic fatty liver) (macrovesicular hepatic steatosis with or without mild inflammation) and NASH (nonalcoholic steatohepatitis) (additionally characterized by inflammation and cellular injury [ballooning], with/without fibrosis, cirrhosis). […] Data from animal studies and clinical studies support the role of proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha) in the early stages of fatty liver, as well as in alcoholic steatohepatitis.

• #32

  https://link.springer.com/article/10.1007/s12291-011-0121-7

  A number of factors are linked with non-alcoholic fatty liver diseases (NAFLD), a condition that ranges from clinically benign fatty liver to its more severe form, non alcoholic steatohepatitis (NASH). […] In this study, we evaluated the role of cytokines secreted from adipose tissue in the pathogenesis and progression of NAFLD. […] NAFLD patients showed elevated levels of pro-inflammatory cytokines tumor necrosis factor (TNF)-, and interleukin (IL)-6, while anti-inflammatory cytokines IL-4 level decreased and IL-10 level remain unchanged; however, TGF-1 level elevated significantly compared to normal subjects. […] In conclusion, pro-inflammatory cytokines play an important link between metabolic and liver disorders in the fat accumulation, and thereby cause IR, inflammation and liver fibrosis.

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

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

  The mechanisms associated with the deposition and maintenance of excess hepatic lipids define an imbalance between the hepatic production and removal of TGs, which are majorly transferred from the liver within VLDLs. Data concerning which toxic lipids induce liver injury in NAFLD and NASH are limited. Agents or factors that stimulate or modulate liver damage in NAFLD can assist to identify potential therapeutic targets. HDLs have been recognized as good cholesterol, essential to the body, which functions to ameliorate various metabolic conditions, including CVDs and NAFLD. Correction and management of the factors involved in the pathophysiology and progression of NAFLD, including hyperlipidaemia, obesity, IR, DM, oxidative stress, lifestyle, inactivity and poor dietary control are the current therapeutic targets for NAFLD. To minimize liver damage in NAFLD, new approaches that target HDL-induced drugs and cholesterol metabolism pathways may be helpful in lowering hepatic cholesterol content.

• #34 ePrints

  https://eprints.ncl.ac.uk/226023

  Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver dysfunction in the Western world and is increasing owing to its close association with obesity and insulin resistance. […] NAFLD represents a spectrum of liver disease that, in a minority of patients, can lead to progressive nonalcoholic steatohepatitis (NASH), fibrosis, and ultimately hepatocellular carcinoma and liver failure. […] NAFLD is a complex trait resulting from the interaction between environmental exposure and a susceptible polygenic background and comprising multiple independent modifiers of risk, such as the microbiome. […] The molecular mechanisms that combine to define the transition to NASH and progressive disease are complex, and consequently, no pharmacological therapy currently exists to treat NASH. […] A better understanding of the pathogenesis of NAFLD is critical if new treatments are to be discovered.

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