Pyroptosis is a type of programmed cell death mediated by a multiprotein complex called the inflammasome through the pro‐inflammatory activity of gasdermin D. This study aimed to recognize the final ...biological product that leads to pore formation in the cell membrane, lysis, pro‐inflammatory cytokines release, and the establishment of an immune response. An exhaustive search engine investigation of an elevated immune response can induce a sustained inflammation that directly links this mechanism to non‐alcoholic fatty liver disease and its progression to non‐alcoholic steatohepatitis. Clinical studies and systematic reviews suggest that gasdermin D is a critical molecule between the immune response and the disease manifestation, which could be considered a therapeutic target for highly prevalent diseases characterized by presenting perpetuated inflammatory processes. Both basic and clinical research show evidence on the expression and regulation of the inflammasome–gasdermin D–pyroptosis trinomial for the progression of non‐alcoholic fatty liver disease to non‐alcoholic steatohepatitis.
Nonalcoholic fatty liver disease (NAFLD) is a chronic liver condition that can progress to nonalcoholic steatohepatitis, cirrhosis and cancer. It is considered an emerging health problem due to ...malnourishment or a high-fat diet (HFD) intake, which is observed worldwide. It is well known that the hepatocytes' apoptosis phenomenon is one of the most important features of NAFLD. Thus, this review focuses on revealing, through a proteomics approach, the complex network of protein interactions that promote fibrosis, liver cell stress, and apoptosis. According to different types of in vitro and murine models, it has been found that oxidative/nitrative protein stress leads to mitochondrial dysfunction, which plays a major role in stimulating NAFLD damage. Human studies have revealed the importance of novel biomarkers, such as retinol-binding protein 4, lumican, transgelin 2 and hemoglobin, which have a significant role in the disease. The post-genome era has brought proteomics technology, which allows the determination of molecular pathogenesis in NAFLD. This has led to the search for biomarkers which improve early diagnosis and optimal treatment and which may effectively prevent fatal consequences such as cirrhosis or cancer.
In vitro exposure of liver cells to high concentrations of free fatty acids (FFA) results in fat overload which promotes inflammatory and fibrogenic response similar to those observed in patients ...with Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH). Since the mechanisms of this event have not been fully characterized, we aimed to analyze the fibrogenic stimuli in a new in vitro model of NASH.
HuH7 cells were cultured for 24 h in an enriched medium containing bovine serum albumin and increasing concentrations of palmitic and oleic acid at a molar ratio of 1:2 (palmitic and oleic acid, respectively). Cytotoxic effect, apoptosis, oxidative stress, and production of inflammatory and fibrogenic cytokines were measured.
FFA induces a significant increment in the intracellular content of lipid droplets. The gene expression of interleukin-6, interleukin-8 and tumor necrosis factor alpha was significantly increased. The protein level of interleukin-8 was also increased. Intracellular lipid accumulation was associated to a significant up-regulation in the gene expression of transforming growth factor beta 1, alpha 2 macroglobulin, vascular endothelial growth factor A, connective tissue growth factor, insulin-like growth factor 2, thrombospondin 1. Flow cytometry analysis demonstrated a significant increment of early apoptosis and production of reactive oxygen species.
The exposure of hepatocytes to fatty acids elicits inflammation, increase of oxidative stress, apoptosis and production of fibrogenic cytokines. These data support a primary role of FFA in the pathogenesis of NAFLD and NASH.
The prevalence of hypothyroidism in patients with nonalcoholic fatty liver disease (NAFLD) is high (22.4%). Thyroid hormones (THs) regulate many metabolic activities in the liver by promoting the ...export and oxidation of lipids, as well as de novo lipogenesis. They also control hepatic insulin sensitivity and suppress hepatic gluconeogenesis. Because of its importance in lipid and carbohydrate metabolism, the involvement of thyroid dysfunction in the pathogenesis of NAFLD seems plausible. The mechanisms implicated in this relationship include high thyroid-stimulating hormone (TSH) levels, low TH levels, and chronic inflammation. The activity of the TH receptor (THR)-β in response to THs is essential in the pathogenesis of hypothyroidism-induced NAFLD. Therefore, an orally active selective liver THR-β agonist, Resmetirom (MGL-3196), was developed, and has been shown to reduce liver fat content, and as a secondary end point, to improve nonalcoholic steatohepatitis. The treatment of NAFLD with THR-β agonists seems quite promising, and other agonists are currently under development and investigation. This review aims to shine a light on the pathophysiological and epidemiological evidence regarding this relationship and the effect that treatment with THs and selective liver THR-β agonists have on hepatic lipid metabolism.
Nonalcoholic fatty liver disease (NAFLD) is characterized by fat deposition in hepatocytes, and a strong association with nutritional factors. Dietary fatty acids are classified according to their ...biochemical properties, which confer their bioactive roles. Monounsaturated fatty acids have a dual role in various human and murine models. In contrast, polyunsaturated fatty acids exhibit antiobesity, anti steatosic and anti-inflammatory effects. The combination of these forms of fatty acids-according to dietary type, daily intake and the proportion of n-6 to n-3 fats-can compromise hepatic lipid metabolism. A chemosensory rather than a nutritional role makes bioactive fatty acids possible biomarkers for NAFLD. Bioactive fatty acids provide health benefits through modification of fatty acid composition and modulating the activity of liver cells during liver fibrosis. More and better evidence is necessary to elucidate the role of bioactive fatty acids in nutritional and clinical treatment strategies for patients with NAFLD.
Nonalcoholic fatty liver disease (NAFLD) is increasingly recognised as a condition associated with overweight or obesity that may progress to end-stage liver disease. NAFLD histology resembles ...alcohol-induced liver injury, but occurs in patients with no history of alcohol abuse. NAFLD has a broad spectrum of clinical and histological manifestations, ranging from simple fatty liver to hepatic steatosis with inflammation, advanced fibrosis, and cirrhosis. The inflammatory stage is known as non-alcoholic steatohepatitis (NASH). Recent reports indicate that weight loss induced by bariatric procedures could be beneficial for NASH treatment.
To assess the benefits and harms of bariatric surgery for NASH in obese patients.
We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded to October 2009.
All randomised clinical trials evaluating any bariatric procedure versus no intervention, placebo (sham procedure), or other interventions in patients with NASH regardless of publication status, number of patients randomised, language, or blinding. Quasi-randomised clinical studies were to be considered for the review if no randomised clinical trials were identified. If included, their bias towards positive findings was to be considered.
We extracted data in duplicate, and we planned to analyse the data by intention-to-treat.
We could not find any randomised clinical trials or quasi-randomised clinical studies that fulfilled the inclusion criteria. Our search resulted in twenty-one prospective or retrospective cohort studies, in which improvement on steatosis or inflammation scores was reported. However, four studies also described some deterioration in the degree of fibrosis.
The lack of randomised clinical trials and quasi-randomised clinical studies precludes us to assess the benefits and harms of bariatric surgery as a therapeutic approach for patients with NASH. Limitations of all other studies with inferior design did not allow us to draw any unbiased conclusion on bariatric surgery for treatment of NASH.
•Global obesity epidemic dramatically increased the fatty liver disease prevalence.•In vitro models mimic liver microenvironment reproducing cellular responses to FFA.•HSC activation is ...fat-independent but requires hepatocytes interaction.•The gene regulation of ECM components seems to occur through paracrine mediators.
A complex interplay exists between hepatocytes and hepatic stellate cells (HSC) in hepatic fibrogenesis. The activation of HSCs after liver injury leads to production of extracellular matrix (ECM). Co-culture models could be useful to mimic the liver microenvironment. This study evaluates the effect of free fatty acids (FFA) on HSC cells and the interplay with hepatocytes via both soluble-mediator and cell–cell contact.
The human hepatocyte cell line (HuH7) and HSC cells (LX2) were exposed to FFA for 24h in 3 different experimental set-ups: (A) monoculture of HSC; (B) Transwell® system (effect of soluble mediators); and (C) Simultaneous Co-Culture (SCC) (cell-to-cell connections). Intracellular FFA accumulation was assessed qualitatively (microscopy) and quantitatively (flow cytometry); the activation of HSC (alpha smooth muscle actin, α-SMA) expression of ECM components were quantified by RT-PCR.
FFA exposure induces intracellular fat accumulation in all the experimental set-up but the expression of α-SMA was significantly increased only in SCC. On the contrary, the expression of ECM was substantially decreased in the transwell® system.
The HSC activation is independent of FFA accumulation but requires cell-to-cell interaction with hepatocyte. On the contrary, the gene regulation of ECM components seems to occur through paracrine mediators.
Current approaches to hepatic encephalopathy Vidal-Cevallos, Paulina; Chávez-Tapia, Norberto C.; Uribe, Misael
Annals of hepatology,
November-December 2022, 2022-11-00, 20221101, 2022-11-01, Letnik:
27, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Hepatic encephalopathy (HE) is a brain dysfunction caused by liver insufficiency and/or portosystemic shunts. Between 30%–40% of patients with cirrhosis will present overt HE during their lifetime. ...While the pathophysiology of HE is not entirely understood, three critical factors have been identified: hyperammonaemia, systemic inflammation and oxidative stress by glutaminase gene alterations. Minimal HE is defined by the presence of signs of cognitive abnormalities in a patient without asterixis or disorientation; it can only be diagnosed with neuropsychological or psychometric tests. The diagnosis of overt HE is based on clinical examination with clinical scales. Currently, only overt HE should be routinely treated. The aims of treatment in an acute episode should be to improve the mental status, identify and treat the precipitating factor, reduce duration and limit consequences. Treatment strategies are targeted at reducing ammonia production and/or increasing its elimination. Even though minimal HE has negative effects on the patient's quality of life and effects on prognosis, indications for treatment are still controversial. There are still many unanswered questions regarding the pathophysiology and management of HE. We should also endeavor to develop more accurate and objective diagnostic methods for overt HE that would permit early detection and help improve outcomes on quality of life and economic burden.
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