Liver Fat Tissues Research Articles

Overview of Cellular and Soluble Mediators in Systemic Inflammation Associated with Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is currently the most prevalent chronic liver disease in Western countries, affecting approximately 25% of the adult population. This condition encompasses a spectrum of liver diseases characterized by abnormal accumulation of fat in liver tissue (non-alcoholic fatty liver, NAFL) that can progress to non-alcoholic steatohepatitis (NASH), characterized by the presence of liver inflammation and damage. The latter form often coexists with liver fibrosis which, in turn, may progress to a state of cirrhosis and, potentially, hepatocarcinoma, both irreversible processes that often lead to the patient's death and/or the need for liver transplantation. Along with the high associated economic burden, the high mortality rate among NAFLD patients raises interest, not only in the search for novel therapeutic approaches, but also in early diagnosis and prevention to reduce the incidence of NAFLD-related complications. In this line, an exhaustive characterization of the immune status of patients with NAFLD is mandatory. Herein, we attempted to gather and compare the current and relevant scientific evidence on this matter, mainly on human reports. We addressed the current knowledge related to circulating cellular and soluble mediators, particularly platelets, different leukocyte subsets and relevant inflammatory soluble mediators.

Non-Alcoholic Steatohepatitis (NASH) - A Review of a Crowded Clinical Landscape, Driven by a Complex Disease.

Non-alcoholic steatohepatitis (NASH) is a progressive form of non-alcoholic fatty liver disease (NAFLD), characterized by chronic inflammation and accumulation of fat in liver tissue. Affecting estimated 35 million people globally, NASH is the most common chronic liver condition in Western populations, and with patient numbers growing rapidly, the market for NASH therapy is projected to rise to $27.2 B in 2029. Despite this clinical need and attractive commercial opportunity, there are no Food and Drug Administration (FDA)-approved therapies specifically for this disease. Many have tried and unfortunately failed to find a drug, or drug combination, capable of unravelling the complexities of this metabolic condition. At the time of writing this review, only Zydus Cadila’s new drug application for Saroglitazar had been approved (2020) for NASH therapy in India. However, it is hoped that this dearth of therapy options will improve as several drug candidates progress through late-stage clinical development. Obeticholic acid (Intercept Pharmaceuticals), Cenicriviroc (Allergan), Aramchol (Galmed Pharmaceuticals), Resmetirom (Madrigal Pharmaceuticals), Dapagliflozin and Semaglutide (Novo Nordisk) are in advanced Phase 3 clinical trials, while Belapectin (Galectin Therapeutics), MSDC-0602K (Cirius Therapeutics), Lanifibranor (Inventiva), Efruxifermin (Akero) and Tesamorelin (Theratechnologies) are expected to start Phase 3 trials soon. Here, we have performed an exhaustive review of the current therapeutic landscape for this disease and compared, in some detail, the fortunes of different drug classes (biologics vs small molecules) and target molecules. Given the complex pathophysiology of NASH, the use of drug combination, different mechanisms of actions and the targeting of each stage of the disease will likely be required. Hence, the development of a single therapy for NASH seems challenging and unlikely, despite the plethora of later stage trials due to report. We therefore predict that clinical, patient and company interest in pipeline and next-generation therapies will remain high for some time to come.

Amylin and Calcitonin: Potential Therapeutic Strategies to Reduce Body Weight and Liver Fat.

The hormones amylin and calcitonin interact with receptors within the same family to exert their effects on the human organism. Calcitonin, derived from thyroid C cells, is known for its inhibitory effect on osteoclasts. Calcitonin of mammalian origin promotes insulin sensitivity, while the more potent calcitonin extracted from salmon additionally inhibits gastric emptying, promotes gallbladder relaxation, increases energy expenditure and induces satiety as well as weight loss. Amylin, derived from pancreatic beta cells, regulates plasma glucose by delaying gastric emptying after meal ingestion, and modulates glucagon secretion and central satiety signals in the brain. Thus, both hormones seem to have metabolic effects of relevance in the context of non-alcoholic fatty liver disease (NAFLD) and other metabolic diseases. In rats, studies with dual amylin and calcitonin receptor agonists have demonstrated robust body weight loss, improved glucose tolerance and a decreased deposition of fat in liver tissue beyond what is observed after a body weight loss. The translational aspects of these preclinical data currently remain unknown. Here, we describe the physiology, pathophysiology, and pharmacological effects of amylin and calcitonin and review preclinical and clinical findings alluding to the future potential of amylin and calcitonin-based drugs for the treatment of obesity and NAFLD.

Critical Role of NFκB in the Pathogenesis of Non-alcoholic Fatty Liver Disease: A Widespread Key Regulator.

Non-alcoholic fatty liver disease is a chronic metabolic disorder representing the most common cause of chronic liver disease in western civilization and one of the main causes of cirrhosis with a significant impact on all-cause mortality in the most advanced phases. It is characterized by hepatic fat accumulation in the absence of significant ethanol consumption, virus infection or other specific causes of liver disease. Accumulation of fat in liver tissue occurs as a consequence of the imbalance between overconsumption of high-fat diet and increased de novo lipogenesis and decreased lipid disposal. Novel dietary and pharmacological therapies for the prevention of fatty liver disease and the progression to cirrhosis are an actual field of study but still poorly understood. In this perspective, the current review aims to summarise and clarify the transcription factor NFκB effects, which may exert among non-alcoholic fatty liver diseases and their progression. Through extensive previous research, it has become clear that several signaling pathways are involved: metabolic dysregulation (such as free fatty acids increase, adipokine alteration, insulin resistance), oxidative stress and inflammation contribute together in a "vicious circle" to the pathogenesis of non-alcoholic fatty liver diseases. Within this, NFκB signaling is a primary factor in inflammatory reactions and diseases, with important molecular connections between metabolic, oxidative, immune and inflammation systems.

ApoE deficiency promotes non-alcoholic fatty liver disease in mice via impeding AMPK/mTOR mediated autophagy

AimThis work was to investigate the relationship between ApoE and autophagy regulated by AMPK/mTOR pathway in the pathological process of NAFLD. Main methodsBoth WT and ApoE−/− mice were divided into two groups and allocated into either a normal chow (ND) or a high-fat diet (HFD) for 8 weeks. After that, we detected the indicators of lipid accumulation, hepatic injury, mitochondrial function hallmark, autophagy, apoptosis, inflammation, and oxidative stress by commercially available kits, immunohistochemistry, immunofluorescent staining, and western blot. Key findingWe found the lipid levels of serum and liver, and hepatic injury were significantly increased in the ApoE−/−-HFD group compared to other groups. ApoE−/− mice exhibited increased deposition of fat in liver tissue. The PGC1α, NRF1, ATP, p-AMPK, AMPK, Beclin1, and LC3 levels were downregulated and ROS, p-mTOR, and mTOR were increased in the ApoE−/−-HFD group compared to WT-HFD group. When treated with AMPK and autophagy activators, AICAR and rapamycin, these pathologies and protein levels can be rescued. The expression levels of apoptosis-related proteins, inflammation, and oxidative stress were increased in the ApoE−/−-HFD group compared to the WT-HFD group. SignificanceOur results indicated that ApoE deficiency can regulate AMPK/mTOR pathway, which leads to NAFLD most likely by modulating hepatic mitochondrial function.

Effect of Some Alcoholic Extracts in Reducing the Fat Content of the Liver Tissue in Rat

Objective: This research was carried out in rats in a special place of the laboratory of histopathological diseases in the period 6/9/2018 until 23/11/2018, this study to detect effect of the addition of the alcohol extract of ginger in the reduction of fat in liver tissue of rats. Method: Eight groups and replicates for each group. The groups were homogenous in weights and were placed in 13 cages. Each group consisted of 10 rat and at 5 fares each. In the first treatment, rat were fed on regular feeding without adding and feeding rats in the second treatment sessions add to it the alcoholic extract of ginger in Turkey 150 mg / kg. The third group is the same as the normal food after adding the alcohol extract of ginger at a concentration of 300 mg / kg. Results: The results of the study showed a high morale in the rates of reduction of fat in the liver tissue of rat fed on the alcohol extract of the ginger and improved the conversion factor of food by adding the extract of alcohol extract of each of the ginger.

Pimpinella anisum L. fruit: Chemical composition and effect on rat model of nonalcoholic fatty liver disease

Background:Nonalcoholic fatty liver disease (NAFLD) includes a group of chronic liver disorders caused by irregular accumulation of fat in liver tissue. The current study aimed to evaluate chemical composition and the effect of fruit extract and essential oil of Pimpinella anisum in experimental model of NAFLD.Materials and Methods:Sixty rats were randomly divided into ten groups, six in each group. NAFLD was induced in rats using choline-deficient diet for 90 days, followed by 30 days of treatment with 25, 50, 100, and 200 mg/kg/day of hydroethanolic extract (AE) as well as 0.125, 0.25, and 0.5 mg/kg/day of essential oil (AO). Blood samples were collected in the final day, and lipid profile, aspartate aminotransferase (AST), alanine aminotransferase (ALT) as well as biomarkers of oxidative damage including myeloperoxidase, lipid peroxidation, total thiol molecules, and ferric-reducing ability of plasma were measured. Liver tissue sections of the sacrificed rats were also assessed histologically.Results:AE and AO significantly reversed increase in the plasma levels of total cholesterol, low-density lipoprotein, and triacylglycerol and decrease in high-density lipoprotein level in a dose-dependent manner (P < 0.05). Serum levels of AST and ALT were also significantly modified by treatment with AE and AO (P < 0.05). Biomarkers of oxidative stress were modulated by administration of AE and AO (P < 0.05). Histological assessments also confirmed the effectiveness of treatments by reduced macrovesicular steatohepatitis.Conclusion:It could be concluded that P. anisum fruit extract and essential oil have beneficial effects in the treatment of NAFLD. Further studies are necessary to confirm safety and efficacy of this medicinal plant in clinical setting.

P1016 : Factors associated with the development of fatty liver or glucose intolerance

measuring different quantities and so bias cannot be assessed directly. The recently cleared (FDA, CE Mark, and TGA) HepaFatScan MRI method reports a volumetric fraction of liver tissue that is fat, a measure that can be directly compared with measurements from biopsy histological sections. This study measures the degree of bias of the HepaFat-Scan method against unbiased stereological measurements from biopsies. Stereological analysis (SA) is a method of obtaining unbiased estimates of volume fractions of a phase of material in a 3D matrix from a cross section through the matrix. Methods: Volumetric fractions of fat in liver tissue of 59 patients (autoimmune hepatitis 3, alcoholic liver disease 2, viral hepatitis 16, NAFLD 10, NASH 17, normal 3, primary sclerosing cholangitis 4, other 4) recruited from the hepatology outpatient clinics at Fremantle and Sir Charles Gairdner Hospitals (Western Australia) were measured by SA of digital images of histological sections of liver biopsies and with non-invasive HepaFat-Scan measurements. Bland–Altman (BA) statistics were used to assess the bias between the two methods of measurement. A steatosis grade for each biopsy was also assessed by an experienced hepatopathologist. ROC curve analysis was used to determine sensitivity and specificity of HepaFat-Scan for predicting steatosis grade. Results: Figure 1 shows a plot of the volumetric fraction of fat measured by HepaFat-Scan plotted against that measured by SA of biopsy histological sections. The straight line is the line of equivalence (not a fitted regression line). BA analysis indicates a small systematic bias with HepaFat-Scan reporting volumetric liver fat fractions 1.4% higher than SA of biopsy. Sensitivities, specificities and areas under ROC curve for HepaFat-Scan predicting steatosis grade >0 were 97%, 96%, and 0.963; >1 were 100%, 94%, and 0.996; and >2 were 100%, 88%, and 0.971. Conclusions: The 1.4% bias between HepaFat-Scan and SA of biopsy is not clinically significant since it represents less than 5% of the overall range of fat fractions measured. The observed high sensitivities and specificities indicate that overall accuracy of HepaFat-Scan is sufficient for clinical patient management.

Atractylodes macrocepala KOIDZ.(백출) 추출물의 급성 경구투여 독성 연구

Atractylodes macrocepala KOIDZ. (AmK) is a herbal medicine and resources of functional food which has been used for the treatment of indigestion, anorexia, diarrhea and digestive dysfunction. Recently AmK is frequently used as resources of functional food and whitening cosmetics. In this study was carried out to evaluate the acute oral toxicity of Amk in Sprague-Dawley(SD) rats. male and female rats were administered orally with Amk extract of 1,000 mg/kg (low dosage group), 2,000 mg/kg (middle dosage group) and 4,000 mg/kg (high dosage group). We daily observed number of deaths, clinical signs and gross findings for 7 days. No dead SD rats and no clinical signs were found during the experiment period. Also other specific changes were not found between control and treated groups in hematology and serum biochemistry. But we found out feeble histopathological changes in liver fat tissues. In addition no significant changes of gross bady and individual organs weight. These results suggest that water soluble extract of AmK has not acute oral toxicity and oral value was over 4,000 mg/kg in SD rats.

Neutral and phenolic brominated organic compounds of natural and anthropogenic origin in northeast Atlantic Greenland shark (Somniosus microcephalus)

In the present study, muscle and liver tissue from 10 female Greenland sharks (Somniosus microcephalus) collected in Icelandic waters were analyzed for neutral and phenolic brominated organic compounds, including polybrominated diphenyl ethers (PBDEs) and the structurally related methoxylated (MeO) and hydroxylated (OH) PBDEs. Hydroxylated PBDEs exist both as natural products and as metabolites of the anthropogenic PBDEs, whereas MeO-PBDEs appear to exclusively be of natural origin. Other compounds examined were 2',6-dimethoxy-2,3',4,5'-tetrabromodiphenyl ether (2',6-diMeO-BDE68), 2,2'-dimethoxy-3,3',5,5'-tetrabromobiphenyl (2,2'-diMeO-BB80), 2,4,6-tribromoanisol (2,4,6-TBA) and 2,4,6-tribromophenol, all of natural origin, although 2,4,6-TBA and its phenolic counterpart may also be of anthropogenic origin. The major brominated organic compound was 6-MeO-BDE47, and ΣMeO-PBDE ranged from 49 to 210 ng/g fat in muscle and from 55 to 200 ng/g fat in liver tissue. Total concentrations of PBDEs were lower than ΣMeO-PBDE, in all but one sample, ranging between 7.3 to 190 and 9.9 to 200 ng/g fat in muscle and liver, respectively, and major congeners were BDE-47, BDE-99, and BDE-100. Polybrominated diphenyl ethers were analyzed using both high- and low-resolution mass spectrometry (MS) as a quality assurance, and the results from this comparison were acceptable. In accordance with previous work on Greenland sharks, no size/age-related accumulation was observed. Differences seen in concentrations were instead assumed to be a reflection of different feeding habits among the individuals. Phenolic compounds were only formed/retained in trace amounts in the Greenland shark. Among the phenolic compounds studied were 6-OH-BDE47, 2'-OH-BDE68, and 2,4,6-tribromophenol, all detected in liver and the latter two in muscle.

Biochemical determination of lipid content in hepatic steatosis by the Soxtec method

To establish a quantitative method to measure the amount of lipids. The livers of 53 male Wistar rats (225 g) with different degrees of hepatic steatosis were studied. This model of hepatic steatosis was based on a high carbohydrate, fat-free modified diet. Biopsies were classified into four grades depending on fat accumulation, using the Kleiner and Brunt classification. Total fat was studied by the Soxtec method (Soxtec 2050 Auto Fat Extraction System), and agreement between both assays was assessed by calculating the kappa coefficient. According to the histological classification, 38% of rats presented grade 0, 21% grade 1, 22% grade 2 and 20% grade 3. The amount of fat per 100 g tissue was 2.60 +/- 0.64 g for grade 0, 3.87 +/- 1.59 g for grade 1, 5.82 +/- 1.37 g for grade 2 and 8.68 +/- 2.30 g for grade 3. Statistically significant differences were found between the mean values for each of the histological grades (P < 0.05). The correlation for the quantification of fat in the liver between both assays was moderate (kappa = 0.60). The biochemical quantification of fat in liver tissue by the Soxtec method was correlated with the histological classification, although the agreement between the two tests was only moderate.

Focal iron sparing and focal fat sparing of liver in patients with hemosiderosis: diagnosis by combination of r2* relaxometry and fat fraction calculation by mri.

To demonstrate magnetic resonance imaging (MRI) findings of the focal sparing of iron and fat in liver tissue in patients with hepatic iron overload. We retrospectively reviewed 48 liver MRIs performed in patients with hemosiderosis from 2007-2009. We selected five (10%) of these patients based on the observation of focal signal abnormalities in the posterior aspect of segment 4, anterior to the portal vein, on in- and out-of-phase T1-weighted gradient-echo images. To further characterize this signal abnormality in segment 4, we calculated the simultaneous proton density fat fraction and R2* relaxometry using the investigational version of a quantitative chemical shift-based water-fat separation method known as IDEAL-IQ with a multiecho gradient echo sequence. Visual assessment and objective measurements were performed for the focal sparing of iron and fat. The diagnoses of the five patients included thalassemia (n=3), aplastic anemia (n=1), and myelodosysplastic syndrome (n=1). The focal sparing of iron was hypointense on R2* relaxometry compared to the rest of the liver. Fat fraction images failed to demonstrate a heterogeneous fat distribution. The focal sparing of fat in the liver with iron overload appeared as a reduced fat-containing area (fat fraction, 4%) in segment 4 compared to the remainder of the left lobe (fat fraction, 12%). The R2* map revealed no difference between the focal fat-sparing area and the rest of the liver. Areas in which focal fat and iron sparing occurred were not visible on post-contrast and diffusion-weighted images. Focal fat and iron sparing in patients with liver siderosis can mimic a lesion. Quantitative MRI techniques can help to characterize abnormal signal changes in segment 4 of the liver in patients with hepatic iron overload and can eliminate the need for biopsy of pseudolesions.

Fatty Liver Disease: MR Imaging Techniques for the Detection and Quantification of Liver Steatosis

Fatty liver disease is the most common cause of chronic liver disease in the United States. Noninvasive detection and quantification of fat is becoming more and more important clinically, due in large part to the growing prevalence of nonalcoholic fatty liver disease. Steatosis, the accumulation of fat-containing vacuoles within hepatocytes, is a key histologic feature of fatty liver disease. Liver biopsy, the current standard of reference for the assessment of steatosis, is invasive, has sampling errors, and is not appropriate in some settings. Several magnetic resonance (MR) imaging-based techniques--including chemical shift imaging, frequency-selective imaging, and MR spectroscopy--are currently in clinical use for the detection and quantification of fat-water admixtures, with each technique having important advantages, disadvantages, and limitations. These techniques permit the breakdown of the net MR signal into fat and water signal components, allowing the quantification of fat in liver tissue, and are increasingly being used in the diagnosis, treatment, and follow-up of fatty liver disease.

Lanthanon-induced hepatotoxicity and its prevention by pretreatment with the same lanthanon.

Intravenous injection of the light lanthanon praseodymium nitrate (10 mg/kg) into rats causes a marked liver toxicity which becomes manifest in hypoglycemia, inhibition of RNA and protein synthesis and accumulation of fat in liver tissue. All these effects can be nearly abolished by pretreating rats with a small dose (5 mg/kg) of the same lanthanon. This is neither due to a decreased uptake into the liver nor to an increased excretion rate of the lanthanon. It is assumed that the pretreatment may increase unspecific binding sites or reversibly block them, thus protecting the organism from the irreversible lethal effect.