Markers Of Steatosis Research Articles

Impact of endocrine disruptors on key events of hepatic steatosis in HepG2 cells.

Endocrine-disrupting chemicals (EDCs) may contribute to the rising incidence of metabolic dysfunction-associated steatotic liver disease (MASLD). We investigated the potential of 10 environmentally relevant EDCs to affect key events of hepatic steatosis in HepG2 human hepatoblastoma cells. Increased lipid droplet formation, a key marker of steatosis, was induced by PFOA, bisphenol F, DDE, butylparaben, and DEHP, within the non-cytotoxic concentration range of 1nM-25 μM. Cadmium also induced this effect, but at concentrations impairing cell viability (>1μM). At non-cytotoxic concentrations, these compounds, along with bisphenol A, dysregulated major genes controlling lipid homeostasis. Cadmium, PFOA, DDE, and DEHP significantly upregulated the DGAT1 gene involved in triglyceride synthesis, while butylparaben increased the expression of the FAT/CD36 gene responsible for fatty acid uptake. Bisphenol A downregulated the CPT1A gene involved in fatty acid oxidation. No significant effects on lipid droplet accumulation or lipid metabolism-related genes were observed for PFOS, bisphenol S, and dibutyl phthalate. Among the tested EDCs, lipid accumulation positively correlated with the expression of SREBF1, DGAT1, and CPT1A. These findings provide additional evidence that EDCs can affect MASLD and highlight the utility of in vitro methods in the screening of EDCs with hazardous steatogenic and metabolism-disrupting properties.

Performance of Noninvasive Indices for Discrimination of Metabolic Dysfunction-Associated Steatotic Liver Disease in Young Adults.

Although numerous noninvasive steatosis indices have been developed to assess hepatic steatosis, whether they can be applied to young adults in the evaluation of metabolic dysfunction-associated steatotic liver disease (MASLD) remains uncertain. Data from patients under 35 years of age who visited the Liver Health Clinic at the Armed Forces Goyang Hospital between July 2022 and January 2024 were retrospectively collected. Steatosis was diagnosed on the basis of a controlled attenuation parameter score ≥250 dB/m. MASLD was defined as the presence of steatosis in patients with at least one cardiometabolic risk factor. Among the 1,382 study participants, 901 were diagnosed with MASLD. All eight indices for diagnosing steatosis differed significantly between the MASLD and non-MASLD groups (p<0.001). Regarding the predictive performance, the hepatic steatosis index (HSI), fatty liver index (FLI), Framingham steatosis index, Dallas steatosis index, Zhejiang University index, lipid accumulation product, visceral adiposity index, and triglyceride glucose-body mass index exhibited an area under the curve of 0.898, 0.907, 0.899, 0.893, 0.915, 0.869, 0.791, and 0.898, respectively. The cutoff values for the FLI and HSI were re-examined, indicating a need for alternative cutoff values for the HSI, with a rule-in value of 42 and a rule-out value of 36 in this population. This study presents novel findings regarding the predictive performance of established steatosis markers in young adults. Alternative cutoff values for the HSI in this population have been proposed and warrant further validation.

Body habitus vs. hepatic steatosis: Understanding the drivers of non-diagnostic shear wave elastography

PurposeShear Wave Elastography (SWE) is frequently non-diagnostic in obese patients, a key cohort at risk for liver disease. Subcutaneous fat and hepatic steatosis are suspected drivers, but their relative contribution is unknown. We compare ultrasound-guided attenuation parameter (UGAP), a marker of steatosis, body mass index (BMI), and skin-to-liver capsule distance (SCD) to predict non-diagnostic SWE. Materials and methodsThis IRB approved, single center retrospective study included adults with SWE and diagnostic UGAP exams between June and December 2023. Fasting patients were imaged in supine position with right arm abducted, via an intercostal window during neutral breath hold. The median of 10 measurements in the right lobe was analyzed for SWE and UGAP. SWE measurements were ≥2 cm from the capsule while UGAP depth was fixed at 4 cm from the probe. Exams were considered non-diagnostic for SWE (measured in m/s) if the Interquartile Range/Median Ratio (IQR/M) was >15 % or if diagnostic measurements could not be obtained. UGAP IQR/M > 30 % or complete measurement failure was considered non-diagnostic. Univariate Receiver Operating Characteristic (ROC) curves compared UGAP (dB/cm/MHz), BMI (kg/m2), and SCD (mm) prediction of non-diagnostic SWE by the DeLong test. Results87 participants (48 male) with mean age of 54.7 ± 15.7 years were analyzed. UGAP [OR: 1.63 per 0.1 dB/cm/MHz, p = 0.02, AUC = 0.66], BMI [OR: 1.23, p < 0.001, AUC = 0.77], and SCD [OR: 1.27, p < 0.001, AUC = 0.81) were predictors of non-diagnostic SWE. UGAP prediction of non-diagnostic SWE was similar in subgroups with the measurement region at least 1 cm (OR: 1.64, n = 68), and 2 cm (OR: 1.54, n = 16) from the liver capsule. UGAP was a worse predictor than SCD (p = 0.04), while not significantly different than BMI (p = 0.15). BMI and SCD did not differ in predicting non-diagnostic SWE (p = 0.44). ConclusionOur small preliminary study demonstrated that body habitus and hepatic attenuation, a marker of steatosis, both contribute to non-diagnostic SWE exams, however body wall thickness is the key driver. This informs patient selection for SWE exams and guides future research to mitigate these technical shortcomings. Clinical relevance/applicationPatients with hepatic steatosis and large body habitus are at increased risk of non-diagnostic ultrasound shear wave elastography (SWE) exams. These patients, particularly those with increased body wall thickness, may benefit from liver fibrosis evaluation with alternative approaches following an initial non-diagnostic SWE exam. Researchers working to improve SWE technique should pay particular attention to mitigating attenuation and phase aberration from the body wall as this is the key driver of non-diagnostic exams.

A flavonoid-rich diet is associated with lower risk and improved imaging biomarkers of nonalcoholic fatty liver disease: a prospective cohort study

BackgroundMechanistic studies and short-term randomized trials suggest higher intakes of dietary flavonoids may protect against nonalcoholic fatty liver disease (NAFLD). ObjectivesWe aimed to perform the first population-based study with long-term follow-up on flavonoid consumption, incident NAFLD, and validated NAFLD biomarkers. MethodsIn a prospective study, we assessed the associations between flavonoid intake based on ≥2 24-h dietary assessments and NAFLD risk among 121,064 adults aged 40–69 y by multivariable Cox regression analyses. We further assessed the associations between flavonoid intake and magnetic resonance imaging-derived liver fat (a subset of n = 11,435) and liver-corrected T1 values (cT1; a subset of n = 9570), a marker of steatosis, more sensitive to inflammatory pathology. ResultsOver 10 y of follow-up, 1081 cases of NAFLD were identified. Participants in the highest quartile (Q4) of the flavodiet score reflecting the consumption of foods high in flavonoids, had a 19% lower risk of NAFLD compared to the lowest quartile (Q1) [hazard ratio (HR) (95% confidence interval (CI): 0.81 (0.67, 0.97), P-trend = 0.02)]. Moreover, participants in the Q4 of the flavodiet score had lower liver fat and cT1 values than those in Q1 (liver fat: relative difference Q1 compared with Q4: –5.28%, P-trend = <0.001; cT1: relative difference Q1 compared with Q4: –1.73%, P-trend = <0.001). When compared to low intakes, high intakes of apples and tea were associated with lower NAFLD risk [apples: HR (95% CI): 0.78 (0.67, 0.92), P-trend = <0.01; tea: HR (95% CI): 0.86 (0.72, 1.02), P-trend = 0.03)]. Additionally, when compared to low intakes, high apple, tea, and dark chocolate intakes were significantly associated with lower liver fat values, whereas high tea and red pepper intakes were significantly associated with lower cT1 values. ConclusionsThe consumption of flavonoid-rich foods was associated with a reduced risk of NAFLD among middle-aged adults.

Ultrasound-based steatosis grading system using 2D-attenuation imaging: An individual patient data meta-analysis with external validation.

Noninvasive tools assessing steatosis, such as ultrasonography-based 2D-attenuation imaging (ATI), are needed to tackle the worldwide burden of steatotic liver disease. This one-stage individual patient data (IPD) meta-analysis aimed to create an ATI-based steatosis grading system. A systematic review (EMBASE + MEDLINE, 2018-2022) identified studies, including patients with histologically or magnetic resonance imaging proton-density fat fraction (MRI-PDFF)-verified ATI for grading steatosis (S0 to S3). One-stage IPD meta-analyses were conducted using generalized mixed models with a random study-specific intercept. Created ATI-based steatosis grading system (aS0 to aS3) was externally validated on a prospective cohort of patients with type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (n=174, histologically and MRI-PDFF-verified steatosis). Eleven enrolled studies included 1374 patients, classified into S0, S1, S2, and S3 in 45.4%, 35.0%, 9.3%, and 10.3% of the cases. ATI was correlated with histological steatosis ( r = 0.60; 95% CI: 0.52, 0.67; p < 0.001) and MRI-PDFF ( r = 0.70; 95% CI: 0.66, 0.73; p < 0.001) but not with liver stiffness ( r = 0.03; 95% CI: -0.04, 0.11, p = 0.343). Steatosis grade was an independent factor associated with ATI (coefficient: 0.24; 95% CI: [0.22, 0.26]; p < 0.001). ATI marginal means within S0, S1, S2, and S3 subpopulations were 0.59 (95% CI: [0.58, 0.61]), 0.69 (95% CI [0.67, 0.71]), 0.78 (95% CI: [0.76, 0.81]), and 0.85 (95% CI: [0.83, 0.88]) dB/cm/MHz; all contrasts between grades were significant ( p < 0.0001). Three ATI thresholds were calibrated to create a new ATI-based steatosis grading system (aS0 to aS3, cutoffs: 0.66, 0.73, and 0.81dB/cm/MHz). Its external validation showed Obuchowski measures of 0.84 ± 0.02 and 0.82 ± 0.02 with histologically based and MRI-PDFF-based references. ATI is a reliable, noninvasive marker of steatosis. This validated ATI-based steatosis grading system could be valuable in assessing patients with metabolic dysfunction-associated steatotic liver disease.

Voluntary exercise fails to prevent metabolic dysfunction-associated steatotic liver disease progression in male rats fed a high-fat high-cholesterol diet.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major public health issue with a worldwide prevalence of 30%-32%. In animal models, voluntary exercise may be an alternative to forced physical activity, avoiding stress, potential injuries, and being logistically simpler. Here, we assessed voluntary exercise (Vex) in Sprague-Dawley rats fed a high-fat, high-cholesterol diet for 18 weeks to induce MASLD. We quantified workload (speed and distance) using exercise wheels and evaluated energy expenditure using calorimetric cages. MASLD progression was assessed using circulating and hepatic biochemical and gene markers of steatosis, inflammation, and fibrosis. The animals ran an average of 301 km during the study period, with the average daily distance peaking at 4937 m/day during Weeks 3-4 before decreasing to 757 m/day by the end of the study. Rats exposed to Vex showed no improvement in any of the MASLD-associated features, such as steatosis, inflammation, or fibrosis. Rats exposed to Vex exhibited a higher total energy expenditure during the night phase (+0.35 kcal/h; p = 0.003) without resulting in any effect on body composition. We conclude that, in our experimental conditions, Vex failed to prevent MASLD progression in male Sprague-Dawley rats exposed to a high-fat high-cholesterol diet for 18 weeks.

Assessment of endocrine disruptor impacts on lipid metabolism in a fatty acid-supplemented HepaRG human hepatic cell line

The incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing worldwide. This disease encompasses several stages, from steatosis to steatohepatitis and, eventually, to fibrosis and cirrhosis. Exposure to environmental contaminants is one of the risk factors and an increasing amount of evidence points to a role for endocrine disrupting compounds (EDCs). This study assesses the impact of selected EDCs on the formation of lipid droplets, the marker for steatosis in a hepatic model. The mechanisms underlying this effect are then explored. Ten compounds were selected according to their obesogenic properties: bisphenol A, F and S, butyl-paraben, cadmium chloride, p,p’-DDE, DBP, DEHP, PFOA and PFOS. Using a 2D or 3D model, HepaRG cells were exposed to the compounds with or without fatty acid supplementation. Then, the formation of lipid droplets was quantified by an automated fluorescence-based method. The expression of genes and proteins involved in lipid metabolism and the impact on cellular respiration was analyzed. The formation of lipid droplets, which is revealed or enhanced by oleic acid supplementation, was most effectively induced by p,p’-DDE and DEHP. Experiments employing either 2D or 3D culture conditions gave similar results. Both compounds induced the expression of PLIN2. p,p’-DDE also appears to act by decreasing in fatty acid oxidation. Some EDCs were able to induce the formation of lipid droplets, in HepaRG cells, an effect which was increased after supplementation of the cells with oleic acid. A full understanding of the mechanisms of these effects will require further investigation. The novel automated detection method described here may also be useful in the future as a regulatory test for EDC risk assessment.

Effects of sodium-glucose contrasporter-2 inhibitors and glucagon-like peptide-1 receptor agonists on vascular function and liver steatosis in diabetes

Abstract Background/Introduction Patients with type-2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD) present increase risk of cardiovascular disease. Sodium-glucose contrasporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have been shown to significantly reduce the risk of cardiovascular complications. Purpose The aim of the study was to investigate the effect of treatment with SGLT-2i or GLP-1RA on vascular function and liver steatosis and fibrosis in patients with T2DM and NAFLD. Methods Thirty patients with T2DM and NAFLD (mean age: 57±11 years) were randomized to receive SGLT-2i (dapagliflozin; n=15) or GLP-1RA (dulaglutide; n=15). At baseline and at 6 months post-treatment, we measured: (1) Perfused boundary region (PBR) of the sublingual microvessels with a diameter 5-25μm using Sidestream Dark Field camera (Microscan, Glycocheck). Increased PBR indicates reduced glycocalyx thickness. (2) Pulse wave velocity (PWV) and augmentation index (AI) using Complior (ALAM Medical), (3) NAFLD fibrosis score (NFS), and (4) Controlled attenuation parameter (CAP) score to assess steatosis grade and liver stiffness (E) to evaluate fibrosis score using liver elastography (FibroScan, Echosens). Results At baseline, patients between the two groups had similar age, sex, HbA1c, steatosis grade, fibrosis score and markers of vascular function (p&amp;gt;0.05). Compared with baseline, all patients had reduced PBR, PWV, AI, NFS, CAP and E (p&amp;lt;0.05) after 6-month treatment. In the whole study population, the percentage reduction of markers of steatosis (NFS) correlated with the corresponding decrease in PBR (r=0.34, p=0.040) and PWV (r=0.31, p=0.043) post-treatment. Both treatments with SGLT-2i and GLP-1RA reduced markers of liver steatosis and fibrosis (Table). Conclusion Both treatments with SGLT-2i and GLP-1RA improve vascular function and reduce liver steatosis in patients with T2DM and NAFLD after 6-month treatment.Table

Rotundic acid alleviates hyperlipidemia in rats by regulating lipid metabolism and gut microbiota.

Disturbances in lipid metabolism and dysbiosis of the gut microbiota play an important role in the progression of hyperlipidemia. Previous study indicated that Ilicis Rotundae Cortex possesses anti-hyperlipidemic activity, and rotundic acid (RA) identified as a key active compound to be incorporated into the body. The study aimed to evaluate the anti-hyperlipidemia effects of RA and explored its impact on gut microbiota and lipid metabolism, as well as its possible mechanisms for improving hyperlipidemia. The study methodology included a comprehensive evaluation of the effects of RA on steatosis markers of hyperlipidemia, lipid metabolism, and gut microbiota by assessing biochemical parameters and histopathology, lipidomics, 16S rRNA gene sequencing, and short-chain fatty acid (SCFA) assays. The results showed that RA effectively reduced body weight and the steatosis markers in serum and liver. Moreover, the lipidomic analysis revealed significant changes in plasmatic and hepatic lipid levels, and these were restored by RA. According to the results of 16S rRNA gene sequencing, RA supplementation raised the relative abundance of Bacteroidetes and Proteobacteria while decreasing the relative abundance of Firmicutes. RA significantly boosted the relative abundance of SCFAs by increasing SCFAs-producing bacteria such as Bacteroides, Alloprevotella, Desulfovibrio, etc. In summary, RA could regulate triglyceride metabolism and glycerophospholipid metabolism, restore gut microbiota structure, and increase the relative abundance of SCFAs-producing bacteria to exert its hypolipidemic effects. These findings suggest RA to be a promising therapeutic agent for hyperlipidemia.

The Effect of Orally Administered Δ9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD) on Obesity Parameters in Mice.

Prolonged cannabis users show a lower prevalence of obesity and associated comorbidities. In rodent models, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) from the plant Cannabis sativa L. have shown anti-obesity properties, suggesting a link between the endocannabinoid system (ECS) and obesity. However, the oral administration route has rarely been studied in this context. The aim of this study was to investigate the effect of prolonged oral administration of pure THC and CBD on obesity-related parameters and peripheral endocannabinoids. C57BL/6 male mice were fed with either a high-fat or standard diet and then received oral treatment in ramping doses, namely 10 mg/kg of THC or CBD for 5 weeks followed by 30 mg/kg for an additional 5 weeks. Mice treated with THC had attenuated weight gain and improved glucose tolerance, followed by improvement in steatosis markers and decreased hypertrophic cells in adipose epididymal tissue. Mice treated with CBD had improved glucose tolerance and increased markers of lipid metabolism in adipose and liver tissues, but in contrast to THC, CBD had no effect on weight gain and steatosis markers. CBD exclusively decreased the level of the endocannabinoid 2-arachidonoylglycerol in the liver. These data suggest that the prolonged oral consumption of THC, but not of CBD, ameliorates diet-induced obesity and metabolic parameters, possibly through a mechanism of adipose tissue adaptation.

The Effects of Sodium-Glucose Cotransporter 2-Inhibitors on Steatosis and Fibrosis in Patients with Non-Alcoholic Fatty Liver Disease or Steatohepatitis and Type 2 Diabetes: A Systematic Review of Randomized Controlled Trials.

Type 2 Diabetes Mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD) are part of metabolic syndrome and share multiple causal associations. Both conditions have an alarmingly increasing incidence and lead to multiple complications, which have an impact on a variety of organs and systems, such as the kidneys, eyes, and nervous and cardiovascular systems, or may cause metabolic disruptions. Sodium-glucose cotransporter 2-inhibitors (SGLT2-i), as an antidiabetic class with well-established cardiovascular benefits, and its class members have also been studied for their presumed effects on steatosis and fibrosis improvement in patients with NAFLD or non-alcoholic steatohepatitis (NASH). The MEDLINE and Cochrane databases were searched for randomized controlled trials examining the efficacy of SGLT2-i on the treatment of NAFLD/NASH in patients with T2DM. Of the originally identified 179 articles, 21 articles were included for final data analysis. Dapagliflozin, empagliflozin, and canagliflozin are some of the most used and studied SGLT2-i agents which have proven efficacy in treating patients with NAFLD/NASH by addressing/targeting different pathophysiological targets/mechanisms: insulin sensitivity improvement, weight loss, especially visceral fat loss, glucotoxicity, and lipotoxicity improvement or even improvement of chronic inflammation. Despite the considerable variability in study duration, sample size, and diagnostic method, the SGLT2-i agents used resulted in improvements in non-invasive markers of steatosis or even fibrosis in patients with T2DM. This systematic review offers encouraging results that place the SGLT2-i class at the top of the therapeutic arsenal for patients diagnosed with T2DM and NAFLD/NASH.

Chlorogenic acid attenuates liver apoptosis and inflammation in endoplasmic reticulum stress-induced mice.

The accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER)results in a state known as "ER stress". It can affect the fate of proteins and play a crucial role in the pathogenesis of several diseases. In this study, we investigated the protective effect of chlorogenic acid (CA) on the inflammation and apoptosis of tunicamycin-induced ER stress in mice. We categorized mice into six groups: Saline, Vehicle, CA, TM, CA 20-TM, and CA 50-TM. The mice received CA (20 or 50 mg/kg) before intraperitoneal tunicamycin injection. After 72 hr of treatment, serum biochemical analysis, histopathological alterations, protein and/or mRNA levels of steatosis, and inflammatory and apoptotic markers were investigated by ELISA and/or RT-PCR. We found that 20 mg/kg CA decreased mRNA levels of Grp78, Ire-1, and Perk. Moreover, CA supplementation prevented TM-induced liver injury through changes in lipid accumulation and lipogenesis markers of steatosis (Srebp-1c, Ppar- α , and Fas), and exerted an inhibitory effect on inflammatory (NF- κ B, Tnf- α , and Il-6) and apoptotic markers (caspase 3, p53, Bax, and Bcl2), of liver tissue in ER stress mice. These data suggest that CA ameliorates hepatic apoptosis and inflammation by reducing NF-κB and Caspase 3 as related key factors between inflammation and apoptosis.

Dietary Sodium and Nonalcoholic Fatty Liver Disease: A Systematic Review

(1) Introduction: Restriction in sodium intake is an important strategy for reducing cardiovascular morbidity and mortality, considering the direct influence of high-sodium diet consumption on the development of hypertension and cardiovascular diseases. There are only a few studies dealing with the influence of dietary sodium on the development of nonalcoholic fatty liver disease (NAFLD). In this systematic review, evidence in humans and animal models was compiled in a critical view of the influence of dietary sodium intake patterns on NAFLD markers; (2) Methods: Systematic review of PubMed data. Clinical outcomes included the prevalence/incidence of NAFLD for human studies, and NAFLD markers (hepatic lipogenesis, and markers of steatosis, fibrosis, and inflammation) for animal studies. The protocol was registered at the International Prospective Register of Systematic Review (PROSPERO; CRD42023390447); (3) Results and Conclusion: Seven studies in humans and eight in animals were included. All studies in humans were observational and associated high-sodium intake with NAFLD. However, in animals, both the increased and reduced consumption of sodium negatively influenced markers of liver steatosis, inflammation, and fibrosis.

Prevalence and clinical determinants of non-alcoholic fatty liver disease by liver scores in adults with type 1 diabetes

AimsTo investigate the prevalence and clinical risk factors for non-alcoholic fatty liver disease (NAFLD) in type 1 diabetes (T1DM) by liver scores. MethodsA retrospective, unicenter, cross-sectional analysis was performed of adults with T1DM from 2015 to 2018. Steatosis scores (hepatic steatosis index-HSI, Framingham steatosis index-FSI) and fibrosis scores (FIB-4 index, AST-to-platelet ratio index-APRI) were associated with clinical parameters. ResultsWe identified 447 patients, 38 ± 14.5 yrs, 54 % female, BMI 28 ± 5.9 kg/m2. Liver steatosis was prevalent at 61 % by HSI ≥ 36 and 52 % by FSI ≥ 23. A majority of these individuals had normal liver transaminase levels. The presence of advanced fibrosis was 4 % by APRI > 0.7 and 4 % by FIB-4 > 2.67. BMI ≥ 25 kg/m2 correlated with steatosis scores (P < 0.001) but not fibrosis scores. Older age (≥40 yrs), hypertension, dyslipidemia, and history of cardiovascular disease were associated with steatosis markers. Only 21 % had any abdominal imaging, 2 % had hepatology referral and 1 % had a liver biopsy. Glucagon-like peptide-1 agonist was prescribed in 5 % and thiazolidinedione in 4 %. ConclusionLiver scores indicating steatosis but not fibrosis is common in adults with T1DM with obesity and/or metabolic syndrome, and is associated with older age, hypertension, and dyslipidemia. NAFLD is under-diagnosed and under-investigated; a minority of patients have had any liver evaluation or treatment.

Janus kinase 2 inhibition by pacritinib as potential therapeutic target for liver fibrosis.

Janus kinase 2 (JAK2) signaling is increased in human and experimental liver fibrosis with portal hypertension. JAK2 inhibitors, such as pacritinib, are already in advanced clinical development for other indications and might also be effective in liver fibrosis. Here, we investigated the antifibrotic role of the JAK2 inhibitor pacritinib on activated hepatic stellate cells (HSCs) in vitro and in two animal models of liver fibrosis in vivo . Transcriptome analyses of JAK2 in human livers and other targets of pacritinib have been shown to correlate with profibrotic factors. Although transcription of JAK2 correlated significantly with type I collagen expression and other profibrotic genes, no correlation was observed for interleukin-1 receptor-associated kinase and colony-stimulating factor 1 receptor. Pacritinib decreased gene expression of fibrosis markers in mouse primary and human-derived HSCs in vitro . Moreover, pacritinib decreased the proliferation, contraction, and migration of HSCs. C 57 BL/6J mice received ethanol in drinking water (16%) or Western diet in combination with carbon tetrachloride intoxication for 7 weeks to induce alcoholic or nonalcoholic fatty liver disease. Pacritinib significantly reduced liver fibrosis assessed by gene expression and Sirius red staining, as well as HSC activation assessed by alpha-smooth muscle actin immunostaining in fibrotic mice. Furthermore, pacritinib decreased the gene expression of hepatic steatosis markers in experimental alcoholic liver disease. Additionally, pacritinib protected against liver injury as assessed by aminotransferase levels. This study demonstrates that the JAK2 inhibitor pacritinib may be promising for the treatment of alcoholic and nonalcoholic liver fibrosis and may be therefore relevant for human pathology.

Sucralose consumption ameliorates high-fat diet-induced glucose intolerance and liver weight gain in mice.

Sucralose is one of the most widely used artificial sweeteners used by the food industry to reduce the calorie density of their products. Although broadly regarded as innocuous, studies show contrasting results depending on whether the research subjects are lean or overweight. In this study, we studied the effect of sucralose consumption on glucose homeostasis in a model of obesity. Male C57BL/6J mice were fed ad libitum with control or a high-fat diet (HFD) and drank either water or sucralose (0.1 mg/mL) for 8 weeks. To characterize the ensuing metabolic changes, we evaluated weight gain, glucose and pyruvate tolerance, and physical performance. Also, we assessed markers of steatosis and mitochondrial mass and function in the liver. Our results show that sucralose reduced weight gain, glucose, and pyruvate intolerance, and prevented the decrease in physical performance of HFD-fed mice. In the liver, sucralose also had a positive effect, preventing the decrease in mitochondrial mass exerted by HFD. Altogether, our results indicate that in the context of an obesogenic diet, sucralose has a beneficial effect at the organismal and hepatic levels.

Association of Inflammatory and Metabolic Biomarkers with Mitral Annular Calcification in Type 2 Diabetes Patients.

(1) Background: Type 2 diabetes mellitus (T2DM) contributes to cardiovascular disease and related mortality through the insidious effects of insulin resistance and chronic inflammation. Mitral annular calcification (MAC) is one such degenerative process promoted by T2DM. (2) Methods: This is a post hoc analysis of insulin resistance, inflammation, and hepatic steatosis markers in T2DM patients without atherosclerotic manifestations, but with incidental echocardiographic detection of mild MAC. (3) Results: 138 consenting patients were 49.3% men, 57.86 years old, with a history of T2DM of 6.16 years and HbA1c 8.06%, of whom sixty had mild MAC (43.47%). The statistically significant differences between patients with/without MAC were higher HOMA C-peptide and C-peptide index for insulin resistance, higher TNF-α for inflammation, and lower estimated glomerular filtration rate. High-sensitive C-reactive protein (hsCRP) was significantly associated with insulin resistance and the strength of the relationship was higher in the MAC group. Predictive of MAC were TNF-α, HOMA C-peptide, and especially hepatic steatosis and hypertension. (4) Conclusions: MAC was more prevalent than reported in the literature. Insulin resistance and inflammation were predictive of MAC, but significant markers differ across studies. Widely available routine tests and echocardiographic assessments are useful in the early identification of mitral annular calcifications in diabetes patients.

Liver Inflammation Is Common and Linked to Metabolic Derangements in Persons With Treated Human Immunodeficiency Virus (HIV).

We sought to characterize in people with human immunodeficiency virus (PWH) the potential etiologies of elevated alanine aminotransferase (ALT) levels, which are common and often unexplained. Participants from the longitudinal observational AIDS Clinical Trials Group HAILO cohort without a history of hepatitis C virus (HCV) or hepatitis B virus (HBV) infection nor reported heavy alcohol use were included. Clinical and demographic characteristics, including medication use, the hepatic steatosis index (HSI), and metabolic syndrome (MetS) were compared between participants with and without ALT elevation. Six hundred sixty-two participants were included; 444 (67%) had ≥1 and 229 (35%) ≥2 consecutive ALT elevations during a median of 4.0 years of follow-up. HSI and Hispanic or other (non-White or Black) race/ethnicity were consistently associated with higher odds of abnormal ALT (odds ratio [OR] 1.1 for HSI as a continuous variable, OR 1.9-2.8 for Hispanic/other race/ethnicity for ≥1 or ≥2 ALT elevations); older age and current smoking were associated with lower odds of abnormal ALT. Associations with metabolic disease, as well as with incident HBV and HCV infection, were strengthened by restricting outcomes to persistent and higher degrees of ALT elevation. ALT elevation was common in this cohort of PWH and associated with metabolic disease and hepatic steatosis markers. Nonalcoholic fatty liver disease is likely a common cause of liver inflammation in PWH receiving suppressive antiretrovirals, deserving targeted diagnosis and intervention.

Endoscopic Bariatric Treatment with Duodenal-Jejunal Bypass Liner Improves Non-invasive Markers of Non-alcoholic Steatohepatitis

PurposePeople with obesity often develop non-alcoholic fatty liver disease (NAFLD) and are at high risk of progression to non-alcoholic steatohepatitis (NASH). Few therapies are effective other than bariatric surgery. We therefore analyzed data from duodenal-jejunal bypass liner (DJBL) patients regarding steatosis, fibrosis, and NASH.MethodsConsecutive DJBL patients with type 2 diabetes underwent standardized assessments up to device removal at 48 weeks. These included aspartate and alanine transaminase (AST, ALT), controlled attenuation parameter (CAP, for steatosis), and liver stiffness measurement (LSM, for fibrosis). The NAFLD fibrosis score (NFS), fibrosis-4 score (FIB4), and enhanced liver fibrosis (ELF) test were also used to assess fibrosis and the Fibroscan-AST (FAST) score to assess NASH. Mixed models were used and missing data were accounted for with multiple imputation.ResultsThirty-two patients (18 female, mean age 55.1, mean BMI 40.2 kg/m2) were included. After 48 weeks, the change compared to baseline with 95% CI was a factor 0.74 (0.65 to 0.84) for AST, 0.63 (0.53 to 0.75) for ALT, and a difference of − 0.21 (− 0.28 to − 0.13) for FAST, all with p < 0.001. Fibrosis based on LSM, NFS, and ELF did not change whereas FIB4 exhibited slight improvement. Eight DJBL were explanted early due to device-related complications and eight complications led to hospitalization.ConclusionsOne year of DJBL therapy is associated with relevant improvements in non-invasive markers of steatosis and NASH, but not fibrosis, and is accompanied by a substantial number of complications. Given the lack of alternatives, DJBL deserves further attention.Graphical abstract

Assessment of Noninvasive Markers of Steatosis and Liver Fibrosis in Human Immunodeficiency Virus-Monoinfected Patients on Stable Antiretroviral Regimens.

BackgroundNonalcoholic fatty liver disease (NAFLD) is a major nonacquired immune deficiency syndrome-defining condition for persons with human immunodeficiency virus (PWH). We aimed to validate noninvasive tests for the diagnosis of NAFLD in PWH.MethodsThis is a cross-sectional study of PWH on stable antiretroviral therapy with persistently elevated transaminases and no known liver disease. The area under the receiver operating characteristic curve (AUROC) was calculated to compare the diagnostic accuracy of liver biopsy with abdominal ultrasound, transient elastography (TE) (including controlled attenuation parameter [CAP]), and noninvasive markers of steatosis (triglyceride and glucose index [TyG], hepatic steatosis index [HSI], fatty liver index [FLI]) and fibrosis ([FIB]-4, aminotransferase-to-platelet ratio index [APRI], NAFLD fibrosis score). We developed a diagnostic algorithm with serial combinations of markers.ResultsOf 146 patients with increased transaminase levels, 69 underwent liver biopsy (90% steatosis, 61% steatohepatitis, and 4% F ≥3). The AUROC for steatosis was as follows: ultrasound, 0.90 (0.75–1); CAP, 0.94 (0.88–1); FLI, 0.81 (0.58–1); HSI, 0.74 (0.62–0.87); and TyG, 0.75 (0.49–1). For liver fibrosis ≥F3, the AUROC for TE, APRI, FIB-4, and NAFLD fibrosis score was 0.92 (0.82–1), 0.96 (0.90–1), 0.97 (0.93–1), and 0.85 (0.68–1). Optimal diagnostic performance for liver steatosis was for 2 noninvasive combined models of tests with TyG and FLI/HSI as the first tests and ultrasound or CAP as the second tests: AUROC = 0.99 (0.97–1, P < .001) and 0.92 (0.77–1, P < .001).ConclusionsUltrasound and CAP performed best in diagnosing liver steatosis, and FLI, TyG, and HSI performed well. We propose an easy-to-implement algorithm with TyG or FLI as the first test and ultrasound or CAP as the second test to accurately diagnose or exclude NAFLD.