Wide Spectrum Of Liver Damage Research Articles

Inhibition of the miR-1914-5p increases the oxidative metabolism in cellular model of steatosis by modulating the Sirt1-PGC-1α pathway and systemic cellular activity.

Metabolic associated fatty liver disease (MAFLD) is considered an indicator of metabolic syndrome, which affects millions of people around the world and no effective treatment is currently available. MAFLD involves a wide spectrum of liver damage, that initiates from steatosis (fatty live) and may progress to more complex pathophysiology. Then, details in lipid metabolism controlling should be explored aiming to control the fatty liver. In this context, the miR-1914-5p can be considered a potential biotechnology tool to control lipid metabolism in hepatic cells. This miRNA finds potential mRNA binding sequences in more than 100 molecules correlated with energy production and lipid metabolism pointed in bioinformatic platforms. The present study addressed the miR-1914-5p effects in hepatic HepG2/LX-2 co-cultured cells in a in vitro steatotic environment stablished by the addition of 400 μM of a mixture of oleic and palmitic acids. The analyses demonstrated that the inhibition of the miRNA reduced energetic metabolites such as total lipids, triglycerides, cholesterol and even glucose. In addition, the miR-inhibitor-transfected cells did not present any deleterious effect in cellular environment by controlling reactive oxygen species production (ROS), mitochondrial membrane potential (ΔΨm) and even the pro-inflammatory environment. Moreover, the functional effect of the investigated miR, suggested its close connection to the modulation of Sirt-1-PGC1-α pathway, a master switch metabolic route that controlls cellular energetic metabolism. Our assays also suggested a synergistic effect of this miR-1914-5p in cell metabolism, which should be considered as a strong candidate to control steatotic environment in future clinical trials.

What Do NAFLD, Liver Fibrosis, and Inflammatory Bowel Disease Have in Common? Review of the Current Literature

Liver disease is one of the most common extraintestinal manifestations of inflammatory bowel disease (IBD). Often the course of liver disease is associated with an exacerbation of the underlying disease (Crohn's Disease/Ulcerative Colitis). Nonalcoholic steatohepatitis encompasses a wide spectrum of liver damage. The most common form is nonalcoholic fatty liver disease (NAFLD) (75-80%), and the less common but more dangerous form is nonalcoholic steatohepatitis (NASH). NAFLD is now the most common cause of chronic liver disease in developed countries and the leading indication for liver transplantation in the United States. Genetic, demographic, clinical, and environmental factors can play a role in the pathogenesis of NAFLD. The increasing prevalence of NAFLD is associated with a widespread obesity epidemic, metabolic complications, including hypertension, type 2 diabetes, and dyslipidaemia. Some of the most common manifestations of IBD are liver, biliary tract, and gallbladder diseases. The liver fibrosis process has a complex pathophysiology and is often dependent on exogenous factors such as the treatment used and endogenous factors such as the gut microbiome. However, the factors that link IBD and liver fibrosis are not yet clear. The main purpose of the review is to try to find links between IBD and selected liver diseases and to identify knowledge gaps that will inform further research.

Non-Invasive Diagnostic Test for Advanced Fibrosis in Adolescents With Non-Alcoholic Fatty Liver Disease.

IntroductionNon-alcoholic fatty liver disease (NAFLD) is a multifaceted disease that includes a wide spectrum of liver damage. The presence and the degree of fibrosis are considered important factors for the prognosis of NAFLD and in predicting the risk of developing cirrhosis. Our aim was to evaluate the usefulness of four fibrosis scores (aspartate aminotransferase/Platelet Index [APRI], FIB-4, NAFLD Fibrosis Score [NFS], and Hepamet) in predicting different degrees of fibrosis among children with biopsy-proven NAFLD.MethodsAbout 286 adolescents [mean age 14.3 years ± 2.5; 154 (53.6%) males], referred between January 2014 and December 2019, with biopsy-proven NAFLD were enrolled.ResultsAbout 173 (60.4%) patients presented fibrosis at histological analysis. In particular: 140 (49.3%) patients had F = 1, 31 (10.8%), had F = 2 and 2 (0.66%) had F = 3. APRI (AUROC 0.619, 95% CI 0.556–0.679) and Hepamet (AUROC 0.778, 95% CI 0.722–0.828) scores had significant (p < 0.001) accuracy to distinguish subjects with fibrosis; while NFS and FIB-4 had not. APRI had a positive predictive value (PPV) of 62.77% (95% CI 57.96–67.35) and an negative predictive value (NPV) of 52.01% (95% CI 46.54–57.43); Hepamet a PPV of 63.24% (95% CI 59.95–66.41) and an NPV of 61.29% (52.9–69.01).ConclusionsOur study showed that Hepamet and APRI perform better than NFS and FIB-4 for identifying fibrosis in patients with NAFLD, but do not have PPVs so high to be considered diagnostic. Therefore, they cannot be employed, in children, for a certain diagnosis of fibrosis or its progression and cannot replace liver biopsy as the gold diagnostic standard. It is, therefore, necessary to continue to research and develop new markers of exclusive fibrosis.

Emerging advances in the pharmacologic treatment of nonalcoholic steatohepatitis and related cirrhosis.

The prevalence of nonalcoholic fatty liver disease (NAFLD) is rapidly growing throughout the world. Nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD, is likely to become the leading cause of cirrhosis and etiology for liver transplantation in future decades in the Western World. Most patients with NAFLD have some components of metabolic syndrome, including obesity, insulin resistance, dyslipidemia, and hypertension. NAFLD encompasses a wide spectrum of liver damage, ranging from simple steatosis to NASH, that can progress to advanced liver disease, as well as hepatocellular carcinoma. Unfortunately, the options for the pharmacological treatment of NASH are still very limited. Nonetheless, several classes of therapies have shown promise, and are currently being evaluated in large phase 2b and phase 3 trials, creating some hope that selected agents will be approved in the coming years. As NASH is a heterogeneous disease, multiple mechanistic pathways are being targeted to achieve optimal treatment response. Combination therapy is also on the horizon, where 2 or more drugs targeting different mechanistic pathways are being used to boost the clinical response. In this review, we first present the current concept of the pathophysiology of NASH, focusing on the pathways currently targeted in clinical trials. We then present the pharmacological agents that are being evaluated in phase IIb of clinical development and beyond, using histological outcomes, and finally we present preliminary results from the combination trials that have already been initiated.

Significance of Simple Steatosis: An Update on the Clinical and Molecular Evidence.

Non-alcoholic fatty liver disease (NAFLD) is defined clinicopathologically by the accumulation of lipids in >5% of hepatocytes and the exclusion of secondary causes of fat accumulation. NAFLD encompasses a wide spectrum of liver damage, extending from simple steatosis or non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH)—the latter is characterized by inflammation and hepatocyte ballooning degeneration, in addition to the steatosis, with or without fibrosis. NAFLD is now the most common cause of chronic liver disease in Western countries and affects around one quarter of the general population. It is a multisystem disorder, which is associated with an increased risk of type 2 diabetes mellitus as well as liver- and cardiovascular-related mortality. Although earlier studies had suggested that NAFL is benign (i.e., non-progressive), cumulative evidence challenges this dogma, and recent data suggest that nearly 25% of those with NAFL may develop fibrosis. Importantly, NAFLD patients are more susceptible to the toxic effects of alcohol, drugs, and other insults to the liver. This is likely due to the functional impairment of steatotic hepatocytes, which is virtually undetectable by current clinical tests. This review provides an overview of the current evidence on the clinical significance of NAFL and discusses the molecular basis for NAFL development and progression.

Circulating microbiota-derived metabolites: a \u201cliquid biopsy?

Background/ObjectivesNon-alcoholic fatty liver disease (NAFLD) causes a wide spectrum of liver damage, from simple steatosis (SS) to cirrhosis. SS and non-alcoholic steatohepatitis (NASH) cannot be distinguished by clinical or laboratory features. Dysregulation of the gut microbiota is involved in NASH pathogenesis. The aim of this study was to assess the relationship between microbiota-derived metabolites and the degrees of NAFLD; also, to investigate whether these metabolites could be included in a panel of NASH biomarkers.Subjects/MethodsWe used liquid chromatography coupled to triple-quadrupole-mass spectrometry (LC-QqQ) analysis to quantify choline and its derivatives, betaine, endogenous ethanol, bile acids, short-chain fatty acids and soluble TLR4 in serum from women with normal weight (n = 29) and women with morbid obesity (MO) (n = 82) with or without NAFLD. We used real-time polymerase chain reaction (RT-PCR) analysis to evaluate the hepatic and intestinal expression level of all genes studied (TLR2, TLR4, TLR9, LXRα, SREBP1C, ACC1, FAS, PPARα, CPT1α, CROT, SREBP2, ABCA1, ABCG1 and FXR in the liver; TLR2, TLR4, TLR5, TLR9, GLP-1R, DPP-4, FXR and PPARɣ in the jejunum) in 82 women with MO with normal liver histology (NL, n = 29), SS (n = 32), and NASH (n = 21).ResultsHepatic FAS, TLR2, and TLR4 expression were overexpressed in NAFLD patients. TLR2 was overexpressed in NASH patients. In women with MO with NAFLD, we found upregulation of intestinal TLR9 expression and downregulation of intestinal FXR expression in women with NASH. Circulating TMAO, glycocholic acid and deoxycholic acid levels were significantly increased in NAFLD patients. Endogenous circulating ethanol levels were increased in NASH patients in comparison to those in SS patients.ConclusionsThese findings suggest that the intestine participates in the progression of NAFLD. Moreover, levels of certain circulating microbiota-related metabolites are associated with NAFLD severity and could be used as a “liquid biopsy” in the noninvasive diagnosis of NASH.

The Epidemiology, Risk Profiling and Diagnostic Challenges of Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of liver damage from the more prevalent (75%–80%) and nonprogressive nonalcoholic fatty liver (NAFL) category to its less common and more ominous subset, nonalcoholic steatohepatitis (NASH). NAFLD is now the most common cause of chronic liver disease in the developed world and is a leading indication for liver transplantation in United States (US). The global prevalence of NAFLD is estimated to be 25%, with the lowest prevalence in Africa (13.5%) and highest in the Middle East (31.8%) and South America (30.4%). The increasing incidence of NAFLD has been associated with the global obesity epidemic and manifestation of metabolic complications, including hypertension, diabetes, and dyslipidemia. The rapidly rising healthcare and economic burdens of NAFLD warrant institution of preventative and treatment measures in the high-risk sub-populations in an effort to reduce the morbidity and mortality associated with NAFLD. Genetic, demographic, clinical, and environmental factors may play a role in the pathogenesis of NAFLD. While NAFLD has been linked with various genetic variants, including PNPLA-3, TM6SF2, and FDFT1, environmental factors may predispose individuals to NAFLD as well. NAFLD is more common in older age groups and in men. With regards to ethnicity, in the US, Hispanics have the highest prevalence of NAFLD, followed by Caucasians and then African-Americans. NAFLD is frequently associated with the components of metabolic syndrome, such as type 2 diabetes mellitus (T2DM), obesity, hypertension, and dyslipidemia. Several studies have shown that the adoption of a healthy lifestyle, weight loss, and pro-active management of individual components of metabolic syndrome can help to prevent, retard or reverse NAFLD-related liver damage. Independently, NAFLD increases the risk of premature cardiovascular disease and associated mortality. For this reason, a case can be made for screening of NAFLD to facilitate early diagnosis and to prevent the hepatic and extra-hepatic complications in high risk sub-populations with morbid obesity, diabetes, and other metabolic risk factors.

Non-Alcoholic Fatty Liver Disease in First Degree Relatives of Patients with Nafld

Non Alcoholic Fatty Liver Disease (NAFLD) includes a spectrum of hepatic pathology that resembles alcoholinduced liver disease but develops in individuals who deny a significant history of alcohol ingestion. NAFLD comprises a wide spectrum of liver damage, ranging from simple macrovesicular steatosis to steatohepatitis, cirrhosis and hepatocellular carcinoma. The prevalence of NAFLD has doubled during last 20 years, whereas the prevalence of other chronic liver diseases has remained stable or even decreased. Moreover with increasing incidence and prevalence, the perception of NAFLD being a benign condition of little clinical significance is rapidly changing. Obesity, metabolic syndrome, type 2 diabetes (T2DM) and dyslipidemia are predisposing factors for NAFLD. All these are directly linked with diet and lifestyle of an individual and hence preventable and modifiable. The study was conducted to identify the prevalence of NAFLD among the first degree relatives of a patient already diagnosed with NAFLD. The study demonstrated the increased prevalence of NAFLD among the family members. Further risk factor analysis in the study strengthened the role of diet and lifestyle in the etiology of NAFLD.

Increased Circulating Levels of Alpha-Ketoglutarate in Morbidly Obese Women with Non-Alcoholic Fatty Liver Disease.

BackgroundNon-alcoholic fatty liver disease (NAFLD) causes a wide spectrum of liver damage, ranging from simple steatosis to cirrhosis. However, simple steatosis (SS) and steatohepatitis (NASH) cannot yet be distinguished by clinical or laboratory features. The aim of this study was to assess the relationship between alpha-ketoglutarate and the degrees of NAFLD in morbidly obese patients.Materials and MethodsWe used a gas chromatography-quadruple time-of-flight-mass spectrometry analysis to quantify alpha-ketoglutarate in serum from normal-weight subjects (n = 30) and morbidly obese women (n = 97) with or without NAFLD.ResultsWe found that serum levels of alpha-ketoglutarate were significantly higher in morbidly obese women than in normal-weight women. We showed that circulating levels of alpha-ketoglutarate were lower in lean controls and morbidly obese patients without NAFLD. We also found that alpha-ketoglutarate serum levels were higher in both SS and NASH than in normal liver of morbidly obese patients. However, there was no difference between SS and NASH. Moreover, we observed that circulating levels of alpha-ketoglutarate were associated with glucose metabolism parameters, lipid profile, hepatic enzymes and steatosis degree. In addition, diagnostic performance of alpha-ketoglutarate has been analyzed in NAFLD patients. The AUROC curves from patients with liver steatosis exhibited an acceptable clinical utility. Finally, we showed that the combination of biomarkers (AST, ALT and alpha-ketoglutarate) had the highest accuracy in diagnosing liver steatosis.ConclusionThese findings suggest that alpha-ketoglutarate can determine the presence of non-alcoholic fatty liver in morbidly obese patients but it is not valid a biomarker for NASH.

AMPKα1 overexpression alleviates the hepatocyte model of nonalcoholic fatty liver disease via inactivating p38MAPK pathway

Nonalcoholic fatty liver disease (NAFLD) has a wide spectrum of liver damage with a worldwide prevalence of almost 20%. AMP-activated protein kinase α1 (AMPKα1) is an energy sensor that plays a key role in regulating lipid metabolism of the liver. This study explores the role of AMPKα1 overexpression in a steatotic hepatocyte model. The results displayed that the AMPKα1 overexpression suppressed lipid accumulation in the cytoplasm, decreased triglyceride levels, maintained the survival of steatotic hepatocyte model with decreased cell apoptosis and increased survival rate. Besides, AMPKα1 overexpression promoted the expression of lipid catabolism-related genes, reduced the level of anabolism-related genes, alleviated the inflammatory response by reducing pro-inflammatory cytokines and increasing anti-inflammatory cytokines. Moreover, AMPKα1 overexpression could inhibit the activation of p38 mitogen-activated protein kinase (p38MAPK). Finally, Anisomycin, a frequently-used activator of p38MAPK, reversed the inhibitory effect of pc-AMPKα1 on the expression of p-p38MAPK, suggesting that AMPKα1 overexpression alleviates inflammatory response through the inactivation of p38MAPK. These results indicated that AMPKα1 may serve as a novel target for treatment of NAFLD.

Characterization of an alcoholic hepatic steatosis model induced by ethanol and high-fat diet in rats

Alcoholic liver disease is characterized by a wide spectrum of liver damage, which increases when ethanol is associated with high-fat diets (HFD). This work aimed to establish a model of alcoholic hepatic steatosis (AHS) by using a combination of 10% ethanol and sunflower seeds as the source of HFD. Male rats received water or 10% ethanol and regular chow diet and/or HFD, which consisted of sunflower seeds. The food consumption, liquid intake and body weight of the rats were monitored for 30 days. After this period, blood was collected for biochemical evaluation, and liver samples were collected for histological, mitochondrial enzyme activity and oxidative stress analyses. Our results indicated that the combination of 10% ethanol and HFD induced micro- and macrosteatosis and hepatocyte tumefaction, decreased the levels of reduced glutathione and glutathione S-transferase activity and increased the level of lipoperoxidation and superoxide dismutase activity. The mitochondrial oxidation of NADH and succinate were partially inhibited. Complexes I and II were the main inhibition sites. Hepatic steatosis was successfully induced after 4 weeks of the diet, and the liver function was modified. The combination of 10% ethanol and sunflower seeds as an HFD produced an inexpensive model to study AHS in rats.

Creatine reduces hepatic TG accumulation in hepatocytes by stimulating fatty acid oxidation

Non-alcoholic fatty liver disease encompasses a wide spectrum of liver damage including steatosis, non-alcoholic steatohepatitis, fibrosis and cirrhosis. We have previously reported that creatine supplementation prevents hepatic steatosis and lipid peroxidation in rats fed a high-fat diet. In this study, we employed oleate-treated McArdle RH-7777 rat hepatoma cells to investigate the role of creatine in regulating hepatic lipid metabolism. Creatine, but not structural analogs, reduced cellular TG accumulation in a dose-dependent manner. Incubating cells with the pan-lipase inhibitor diethyl p-nitrophenylphosphate (E600) did not diminish the effect of creatine, demonstrating that the TG reduction brought about by creatine does not depend on lipolysis. Radiolabeled tracer experiments indicate that creatine increases fatty acid oxidation and TG secretion. In line with increased fatty acid oxidation, mRNA analysis revealed that creatine-treated cells had increased expression of PPARα and several of its transcriptional targets. Taken together, this study provides direct evidence that creatine reduces lipid accumulation in hepatocytes by the stimulation of fatty acid oxidation and TG secretion.

Hepatic carbohydrate and lipid metabolism are altered in rats fed creatine‐supplemented diets (LB151)

Non‐alcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of liver damage. Insulin resistance often accompanies NAFLD and these phenomena are hallmarks of the metabolic syndrome. Recently, we reported that creatine supplementation prevents hepatic steatosis, lipid peroxidation and insulin resistance in rats fed a high‐fat diet. In order to examine potential mechanisms underlying these observations, we used McArdle RH‐7777 rat hepatoma cells treated with oleic acid as a model of hepatocyte lipid accumulation. We found that cells cultures with creatine had a dose dependent reduction in cellular TG accumulation. Using radiolabeled tracers we have demonstrated that incubation of hepatoma cells with creatine increases fatty acid oxidation and decreases both fatty acid and TG synthesis. In‐line with increased fatty acid oxidation, analysis of mRNA from hepatoma cells treated with creatine had increased expression of PPARα and its targets CPT1a and LCAD. We have also found that creatine treated hepatoma cells have increased expression of the PEPCK and pyruvate kinase. Our preliminary data suggests that rats fed a creatine‐supplemented high‐fat diet have significantly improved glucose tolerance compared to high‐fat diet fed control animals. Together these data suggest that dietary creatine influences carbohydrate metabolism as well as lipid metabolism.This research is funded by the CIHRGrant Funding Source: Supported by CIHR

Relationship between serum vitamin b12, hyperhomocysteinemia in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) represents a wide spectrum of liver damage and the prevalence is increasing worldwide. Hyper homocysteinemia is implicated as a causative factor of endothelial dysfunction, hepatic steatosis and cardio vascular disease (CVD). Since Vitamin B12 deficiency is one of the most important causative factors of hyper homocysteinemia. This study aims to elucidate serum levels of homocysteine and Vitamin B12 in south indian NAFLD patients. Patient diagnosed to have NAFLD by standard clinical, radiological and biochemical investigations formed the study group. Healthy volunteers formed the control group. Fasting blood samples were collected at Star medical diagnostics and were subjected to biochemical analysis. Vitamin B12 and homocysteine were assayed using chemiluminiscence commercial kits. Liver function tests (LFT), lipid profile and HOMA IR were assayed using auto analyzer. Vitamin B 12 deficiency ( 17.24 micro moles). Elevated ALT was found to be correlated with 67% of Vitamin B12 and 70% of hyper homocysteinemic NAFLD patients respectively. Our results indicate that hyper homocysteinemia may be one of the factors responsible for hepatic steatosis in NAFLD patients.

Prognostic factors for progression of simple steatosis to steatohepatitis in patients with persistent normal and elevated liver enzymes

IntroductionNonalcoholic fatty liver disease (NAFLD) is characterized by a wide spectrum of liver damage, ranging from simple macrovesicular steatosis to steatohepatitis [nonalcoholic steatohepatitis (NASH)], cirrhosis, and liver carcinoma.AimThis study assessed reliable markers of NASH such as clin

Nonalcoholic Fatty Liver Disease: Prevalence, Influence on Age and Sex, and Relationship with Metabolic Syndrome and Insulin Resistance

Nonalcoholic fatty liver disease (NAFLD) is a common condition comprising a wide spectrum of liver damage strongly associated with type 2 diabetes, obesity, and hyperlipidemia. The pathogenesis of fatty liver is multifactorial, and it has been suggested that the presence of insulin resistance (IR) is an essential requirement for the accumulation of hepatocellular fat. Although NAFLD may affect people of any age, in general, increasing age is associated with increasing prevalence. The aim of this study was to determine the prevalence of fatty liver and its influence on age and sex; and to assess the association of different degrees of fatty liver to IR and metabolic syndrome. The study was performed in 8350 alcohol- and virus-negative individuals who underwent routine physical check-up at the health evaluation centre of Mackay Memorial Hospital, from February 2004 to May 2009. They underwent clinical examination, anthropometry, biochemical tests including serum fasting insulin, and routine liver ultrasonography. Steatosis was graded as absent, mild, moderate, or severe. The overall prevalence of fatty liver was 34.40% with the prevalence of fatty liver being significantly higher in males than in females (22.34 vs. 12.06%, p = 0.015). A progressive increase in the means of a homeostasis model assessment of IR (HOMA-IR), body mass index, systolic blood pressure, plasma triglyceride, alanine aminotransferase, low-density lipoprotein-cholesterol and glucose level and decrease in high-density lipoprotein-cholesterol ( p < 0.001 and p < 0.05) was observed from the group without steatosis to the groups with mild, moderate, and severe steatosis. Severe steatosis was associated with the clustering of risk factors for metabolic syndrome. Individuals with metabolic syndrome and a more pronounced HOMA-IR had a higher prevalence of moderate to severe steatosis ( p < 0.001 and p < 0.05) compared to those with HOMA-IR below the median. Fatty liver can be considered as the hepatic consequence of metabolic syndrome, specifically IR. There is a high prevalence of metabolic syndrome and fatty liver among the elderly population. Metabolic disorders are closely related to fatty liver; moreover, fatty liver appears to be a good predictor for the clustering of risk factors for metabolic syndrome.

Ilexgenin A Obtained from Ilex hainanensis Merr. Improves Diet‐Induced Non‐Alcoholic Fatty Liver Disease in Rats

Abstract Preclinical Research Nonalcoholic fatty liver disease (NAFLD) is a common aspect of metabolic syndrome, which includes a wide spectrum of liver damage and is closely associated with insulin resistance and lipid peroxidation. The current study aimed to evaluate the protective effect of Ilexgenin A (IA), obtained from Ilex hainanensis Merr., on NAFLD and investigate the underlying mechanisms. Sprague‐Dawley rats were fed a high‐fat (HF) diet for 3 weeks to induce NAFLD. They were divided into HF diet rats and HF‐IA‐treated rats, which were treated with IA (80 mg/kg p.o.) for 2 weeks. IA alleviated hepatic steatosis and insulin resistance and reduced plasma levels of alanine transaminase, aspartate aminotransferase, triglyceride, total cholesterol, low‐density lipoprotein‐cholesterol, malondialdehyde, interleukin 6, and tumor necrosis factor‐α, while increasing plasma levels of high‐density lipoprotein‐cholesterol and superoxide dismutase (SOD). IA decreased hepatic triglycerides, total cholesterol, malondialdehyde, and restored the abnormal down‐regulation of SOD. IA also decreased Cytochrome P450 2E1 expression and up‐regulated peroxisome proliferator‐activated receptor α (PPARα) expression in liver. These results suggested that IA had the potential to attenuate NAFLD by improving lipid metabolism, insulin resistance, inflammation, and oxidative stress, as well as adjusting the expression of Cytochrome P450 2E1 and PPARα.

Patología de hígado graso no-alcohólico (HGNA) asociada a obesidad: mecanismos patogénicos

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Molecular mechanisms of steatosis in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is the most important cause of chronic liver disease and is considered the hepatic manifestation of the metabolic syndrome associated with diabetes mellitus type 2. The prevalence of NAFLD in the general population reaches 15-20%. It is also estimated that nonalcoholic steatohepatitis (NASH) affects 3% of the population. NAFLD refers to a wide spectrum of liver damage, which ranges from simple steatosis or intracellular triglyceride accumulation, to inflammation (NASH), fibrosis and cirrhosis. The mechanisms involved in the accumulation of triglycerides in the liver and subsequent hepatocellular damage are multifactorial and are not completely understood. However, metabolic changes such as insulin resistance (IR) are developed, being a common factor in the retention of fatty acids (FA) within the hepatocytes with oxidation and production of free radicals at the mitochondrial level, which are capable of causing lipid peroxidation, cytokine production, and necrosis. In addition, there are alterations in the hepatic bioavailability of long chain n-3 polyunsaturated fatty acids, conditions that alter the expression of a series of transcriptional factors involved in lipolytic and lipogenic processes in the liver. A greater knowledge of the etiopathogenic mechanisms of NAFLD is fundamental for the development of future effective therapeutic strategies. The pathophysiological fundamentals of liver steatosis are analyzed in this study.

A novel agonist of PPAR-γ based on barbituric acid alleviates the development of non-alcoholic fatty liver disease by regulating adipocytokine expression and preventing insulin resistance

Non-alcoholic fatty liver disease (NAFLD) is a frequent kind of metabolic syndrome, which included a wide spectrum of liver damage and closely associated with insulin resistance and other metabolic syndromes such as obesity, type II diabetes, hyperglycemia, etc. Recently, a new series of PPARγ ligands based on barbituric acid has been designed, in which 5-(4-(benzyloxy)benzylidene)pyrimidine-2,4,6(1H,3H,5H)-trione (SKLB102) showed a high affinity with PPARγ. The current study aimed to evaluate the protective effect of SKLB102 on NAFLD and investigate the underlying mechanisms. In vivo, oral administration of SKLB102 prevented the pathological development, as demonstrated by reducing liver weight and visceral fat effectively, decreasing the serum levels of alanine transaminase, TNF-α and glucose, diminishing the hepatic triglyceride and malondialdehyde content and recovering the abnormal down-regulation of LDL. Histological examination of liver sections by Oil Red O and H&E staining confirmed the protective effect of SKLB102 on NAFLD. Furthermore, SKLB102 elevated the serum level of adiponectin, reduced the serum level of leptin and prevented insulin resistance. Western blots indicated that SKLB102 increased the hepatic AMPK activities and CPT-1 expression. In vitro, SKLB102 showed the ability of significantly enhancing adiponectin expression and inhibiting leptin expression in 3T3-L1 adipocytes. Furthermore, SKLB102 could promote glucose consumption in HepG2 cells in the presence of 0.1 μM insulin. In conclusion, our current study provided strong evidence that SKLB102 had potent ability to reduce fat deposition and protect liver against NAFLD through regulating adipocytokine expression and preventing insulin resistance, which might be of protective value for the prevention of NAFLD.