Targeting Myeloid-Derived Cells: New Frontiers in the Treatment of Non-alcoholic and Alcoholic Liver Disease

Non-alcoholic fatty liver disease (NAFLD) and Alcoholic Liver Disease (ALD) are major causes of liver-related morbidity and mortality and constitute important causes of liver transplantation. The spectrum of the liver disease is wide and includes isolated steatosis, steatohepatitis, and cirrhosis. The treatment of NAFLD and ALD remains, however, an unmet need, and therefore it is a public health priority to develop effective treatments for these diseases. Alcoholic and non-alcoholic liver disease share common complex pathogenetic pathways that involve different organs and systems beyond the liver, including the gut, the adipose tissue, and the immune system, which cross-talk to generate damage. Myeloid-derived cells have been widely studied in the setting of NAFLD and ALD and are implicated at different levels in the onset and progression of this disease. Among these cells, monocytes and macrophages have been found to be involved in the induction of inflammation and in the progression to fibrosis, both in animal models and clinical studies and they have become interesting potential targets for the treatment of both NAFLD and ALD. The different mechanisms by which these cells can be targeted include modulation of Kupffer cell activation, monocyte recruitment in the liver and macrophage polarization and differentiation. Evidence from preclinical studies and clinical trials (some of them already in phase II and III) have shown encouraging results in ameliorating steatohepatitis, fibrosis, and the metabolic profile, individuating promising candidates for the pharmacological treatment of these diseases. The currently available results of myeloid-derived cells targeted treatments in NAFLD and ALD are covered in this review

The Differential Roles of T Cells in Non-alcoholic Fatty Liver Disease and Obesity

Non-alcoholic fatty liver disease (NAFLD) constitutes a spectrum of disease states characterized by hepatic steatosis and is closely associated to obesity and the metabolic syndrome. In non-alcoholic steatohepatitis (NASH), additionally, inflammatory changes and hepatocellular damage are present, representing a more severe condition, for which the treatment is an unmet medical need. Pathophysiologically, the immune system is one of the main drivers of NAFLD progression and other obesity-related comorbidities, and both the innate and adaptive immune system are involved. T cells form the cellular component of the adaptive immune system and consist of multiple differentially active subsets, i.e., T helper (Th) cells, regulatory T (Treg) cells, and cytotoxic T (Tc) cells, as well as several innate T-cell subsets. This review focuses on the role of these T-cell subsets in the pathogenesis of NAFLD, as well as the association with obesity and type 2 diabetes mellitus, reviewing the available evidence from both animal and human studies. Briefly, Th1, Th2, Th17, and Th22 cells seem to have an attenuating effect on adiposity. Th2, Th22, and Treg cells seem to decrease insulin resistance, whereas Th1, Th17, and Tc cells have an aggravating effect. Concerning NAFLD, both Th22 and Treg cells appear to have an overall tempering effect, whereas Th17 and Tc cells seem to induce more liver damage and fibrosis progression. The evidence regarding the role of the innate T-cell subsets is more controversial and warrants further exploration

Posttranscriptional Regulation of the Human LDL Receptor by the U2-Spliceosome

Background: The low-density lipoprotein receptor (LDLR) in the liver is the major determinant of LDL-cholesterol levels in human plasma. The discovery of genes that regulate the activity of LDLR helps to identify pathomechanisms of hypercholesterolemia and novel therapeutic targets against atherosclerotic cardiovascular disease.Methods: We performed a genome-wide RNA interference screen for genes limiting the uptake of fluorescent LDL into Huh-7 hepatocarcinoma cells. Top hit genes were validated by in vitro experiments as well as analyses of datasets on gene expression and variants in human populations.Results: The knockdown of 54 genes significantly inhibited LDL uptake. Fifteen of them encode for components or interactors of the U2-spliceosome. Knocking down any one of 11 out of 15 genes resulted in the selective retention of intron 3 of LDLR. The translated LDLR fragment lacks 88% of the full length LDLR and is detectable neither in non-transfected cells nor in human plasma. The hepatic expression of the intron 3 retention transcript is increased in non-alcoholic fatty liver disease as well as after bariatric surgery. Its expression in blood cells correlates with LDL-cholesterol and age. Single nucleotide polymorphisms and three rare variants of one spliceosome gene, RBM25, are associated with LDL-cholesterol in the population and familial hypercholesterolemia, respectively. Compared to overexpression of wild type RBM25, overexpression of the three rare RBM25 mutants in Huh-7 cells led to lower LDL uptake.Conclusions: We identified a novel mechanism of post-transcriptional regulation of LDLR activity in humans and associations of genetic variants of RBM25 with LDL-cholesterol levels.</p

A pharmacokinetic study to guide dosing of tenofovir disoproxil fumarate during different modalities of renal replacement therapy

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Plasma BCAA changes in Patients with NAFLD are Sex Dependent 1

International audienceContext: Plasma branched chain amino acid (BCAA) concentrations correlate positively with body mass index (BMI), measures of insulin resistance (IR), and severity of nonalcoholic fatty liver disease (NAFLD). Moreover, plasma BCAA concentrations also differ between the sexes, which display different susceptibilities to cardio-metabolic diseases.Objective: Assess whether plasma BCAA concentrations associate with NAFLD severity independently of BMI, IR, and sex.Patients: Patients visiting the obesity clinic of the Antwerp University Hospital were consecutively recruited from 2006 to 2014.Design and setting: A cross-sectional study cohort of 112 obese patients (59 women and 53 men) was divided into 4 groups according to NAFLD severity. Groups were matched for sex, age, BMI, homeostatic model assessment of IR, and hemoglobin A1c.Main outcome measures: Fasting plasma BCAA concentrations were measured by tandem mass spectrometry using the aTRAQ™ method.Results: In the study cohort, a modest positive correlation was observed between plasma BCAA concentrations and NAFLD severity, as well as a strong effect of sex on plasma BCAA levels. Subgroup analysis by sex revealed that while plasma BCAA concentrations increased with severity of NAFLD in women, they tended to decrease in men. Additionally, only women displayed significantly increased plasma BCAAs with increasing fibrosis.Conclusion: Plasma BCAA concentrations display sex-dimorphic changes with increasing severity of NAFLD, independently of BMI, IR, and age. Additionally, plasma BCAA are associated with significant fibrosis in women, but not in men. These results highlight the importance of a careful consideration of sex as a major confounding factor in cross-sectional studies of NAFLD