Adipose tissue inflammation and liver fat in patients with highly active antiretroviral therapy-associated lipodystrophy

2008 ◽  
Vol 295 (1) ◽  
pp. E85-E91 ◽  
Author(s):  
Ksenia Sevastianova ◽  
Jussi Sutinen ◽  
Katja Kannisto ◽  
Anders Hamsten ◽  
Matti Ristola ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Antiretroviral Therapy ◽  
Highly Active Antiretroviral Therapy ◽  
Liver Fat ◽  
Adipose Tissue Inflammation ◽  
Liver Fat Content ◽  
Abdominal Adipose Tissue ◽  
Highly Active ◽  
Subcutaneous Abdominal Adipose Tissue

In this cross-sectional study, we sought to determine whether gene expression of macrophage markers and inflammatory chemokines in lipoatrophic subcutaneous abdominal adipose tissue and liver fat content are increased and interrelated in human immunodeficiency virus (HIV)-1-positive, highly active antiretroviral therapy (HAART)-treated patients with lipodystrophy (HAART+LD+; n = 27) compared with those without (HAART+LD−; n = 13). The study groups were comparable with respect to age, gender, and body mass index. The HAART+LD+ group had twofold more intra-abdominal ( P = 0.01) and 1.5-fold less subcutaneous ( P = 0.091) fat than the HAART+LD− group. As we have reported previously, liver fat was 10-fold higher in the HAART+LD+ compared with the HAART+LD− group ( P = 0.00003). Inflammatory gene expression was increased in HAART-lipodystrophy: CD68 4.5-fold ( P = 0.000013), tumor necrosis factor (TNF)-α 2-fold ( P = 0.0094), chemokine (C-C motif) ligand (CCL) 2 2.5-fold ( P = 0.0024), CCL3 7-fold ( P = 0.0000017), integrin αM (ITGAM) 3-fold ( P = 0.00067), epidermal growth factor-like module containing, mucin-like, hormone receptor-like (EMR)1 2.5-fold ( P = 0.0038), and a disintegrin and metalloproteinase domain (ADAM)8 3.5-fold ( P = 0.00057) higher in the HAART+LD+ compared with the HAART+LD− group. mRNA concentration of CD68 ( r = 0.37, P = 0.019), ITGAM ( r = 0.35, P = 0.025), CCL2 ( r = 0.39, P = 0.012), and CCL3 ( r = 0.54, P = 0.0003) correlated with liver fat content. In conclusion, gene expression of markers of macrophage infiltration and adipose tissue inflammation is increased in lipoatrophic subcutaneous abdominal adipose tissue of patients with HAART-associated lipodystrophy compared with those without. CD68, ITGAM, CCL2, and CCL3 expression is significantly associated with accumulation of liver fat.

Effects of rosiglitazone on gene expression in subcutaneous adipose tissue in highly active antiretroviral therapy-associated lipodystrophy

2004 ◽  
Vol 286 (6) ◽  
pp. E941-E949 ◽  
Author(s):  
Jussi Sutinen ◽  
Katja Kannisto ◽  
Elena Korsheninnikova ◽  
Rachel M. Fisher ◽  
Ewa Ehrenborg ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Adipose Tissue ◽  
Highly Active Antiretroviral Therapy ◽  
Subcutaneous Adipose Tissue ◽  
Binding Protein ◽  
Lipid Binding ◽  
Liver Fat ◽  
Highly Active ◽  
Subcutaneous Adipose

Highly active antiretroviral therapy (HAART) has improved the prognosis of human immunodeficiency virus (HIV)-infected patients but is associated with severe adverse events, such as lipodystrophy and insulin resistance. Rosiglitazone did not increase subcutaneous fat in patients with HAART-associated lipodystrophy (HAL) in a randomized, double-blind, placebo-controlled trial, although it attenuated insulin resistance and decreased liver fat content. The aim of this study was to examine effects of rosiglitazone on gene expression in subcutaneous adipose tissue in 30 patients with HAL. The mRNA concentrations in subcutaneous adipose tissue were measured using real-time PCR. Twenty-four-week treatment with rosiglitazone (8 mg/day) compared with placebo significantly increased the expression of adiponectin, peroxisome proliferator-activated receptor-γ (PPARγ), and PPARγ coactivator 1 and decreased IL-6 expression. Expression of other genes involved in lipogenesis, fatty acid metabolism, or glucose transport, such as acyl-CoA synthase, adipocyte lipid-binding protein, CD45, fatty acid transport protein-1 and -4, GLUT1, GLUT4, keratinocyte lipid-binding protein, lipoprotein lipase, PPARδ, and sterol regulatory element-binding protein-1c, remained unchanged. Rosiglitazone also significantly increased serum adiponectin concentration. The change in serum adiponectin concentration was inversely correlated with the change in fasting serum insulin concentration and liver fat content. In conclusion, rosiglitazone induced significant changes in gene expression in subcutaneous adipose tissue and ameliorated insulin resistance in patients with HAL. Increased expression of adiponectin might have mediated most of the favorable insulin-sensitizing effects of rosiglitazone in these patients.

scholarly journals Adherence to a plant-based diet in relation to adipose tissue volumes and liver fat content

2020 ◽  
Vol 112 (2) ◽  
pp. 354-363
Author(s):  
Ilka Ratjen ◽  
Jakub Morze ◽  
Janna Enderle ◽  
Marcus Both ◽  
Jan Borggrefe ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Visceral Adipose Tissue ◽  
Fat Distribution ◽  
Abdominal Fat ◽  
Fat Content ◽  
Liver Fat ◽  
Healthy Plant ◽  
Liver Fat Content ◽  
Subcutaneous Abdominal Adipose Tissue ◽  
Visceral Adipose

ABSTRACT Background Better adherence to plant-based diets has been linked to lower risk of metabolic diseases but the effect on abdominal fat distribution and liver fat content is unclear. Objectives We aimed to examine the association between different plant-based diet indices and measures of abdominal fat distribution and liver fat content. Methods In a population-based sample of 578 individuals from Northern Germany (57% male, median age 62 y), diet was assessed with a validated FFQ and an overall, a healthy, and an unhealthy plant-based diet index were derived. Participants underwent MRI to assess volumes of visceral and subcutaneous abdominal adipose tissue and liver signal intensity (LSI), a measure of liver fat content. Fatty liver disease (FLD) was defined as log LSI ≥3.0. Cross-sectional associations of the plant-based diet indices with visceral and subcutaneous abdominal fat volumes, LSI, and FLD were assessed in linear and logistic regression analyses. The most comprehensive model adjusted for age, sex, education, smoking, alcohol, physical activity, energy intake, diabetes, hyperlipidemia, and BMI. Results Higher overall and healthy plant-based diet indices both revealed statistically significant associations with lower visceral and subcutaneous abdominal adipose tissue volumes and with lower odds of FLD in multivariable-adjusted models without BMI. Upon additional adjustment for BMI, only the association of the healthy plant-based diet with visceral adipose tissue remained statistically significant (per 10-point higher healthy plant-based diet index, percentage change in visceral adipose tissue: −4.9%, 95% CI: −8.6%, −2.0%). None of the plant-based diet indices was associated with LSI. The unhealthy plant-based diet index was unrelated to any of the abdominal or liver fat parameters. Conclusions Adherence to healthy plant-based diets was associated with lower visceral adipose tissue. None of the other examined associations remained statistically significant after adjustment for BMI.

scholarly journals Branched-chain amino acid metabolism, insulin sensitivity and liver fat response to exercise training in sedentary dysglycaemic and normoglycaemic men

Diabetologia ◽  
2020 ◽  
Author(s):  
Sindre Lee ◽  
Hanne L. Gulseth ◽  
Torgrim M. Langleite ◽  
Frode Norheim ◽  
Thomas Olsen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Plasma Concentration ◽  
Fat Mass ◽  
Liver Fat ◽  
Liver Fat Content ◽  
Mrna Sequencing ◽  
Branched Chain

Abstract Aims/hypothesis Obesity and insulin resistance may be associated with elevated plasma concentration of branched-chain amino acids (BCAAs) and impaired BCAA metabolism. However, it is unknown whether the insulin-sensitising effect of long-term exercise can be explained by concomitant change in BCAAs and their metabolism. Methods We included 26 sedentary overweight and normal-weight middle-aged men from the MyoGlu clinical trial, with or without dysglycaemia, for 12 weeks of supervised intensive exercise intervention, including two endurance and two resistance sessions weekly. Insulin sensitivity was measured as the glucose infusion rate (GIR) from a hyperinsulinaemic−euglycaemic clamp. In addition, maximum oxygen uptake, upper and lower body strength and adipose tissue depots (using MRI and spectroscopy) were measured, and subcutaneous white adipose tissue (ScWAT) and skeletal muscle (SkM) biopsies were harvested both before and after the 12 week intervention. In the present study we have measured plasma BCAAs and related metabolites using CG-MS/MS and HPLC-MS/MS, and performed global mRNA-sequencing pathway analysis on ScWAT and SkM. Results In MyoGlu, men with dysglycaemia displayed lower GIR, more fat mass and higher liver fat content than normoglycaemic men at baseline, and 12 weeks of exercise increased GIR, improved body composition and reduced liver fat content similarly for both groups. In our current study we observed higher plasma concentrations of BCAAs (14.4%, p = 0.01) and related metabolites, such as 3-hydroxyisobutyrate (19.4%, p = 0.034) in dysglycaemic vs normoglycaemic men at baseline. Baseline plasma BCAA levels correlated negatively to the change in GIR (ρ = −0.41, p = 0.037) and $$ \dot{V}{\mathrm{O}}_{2\max } $$ V ̇ O 2 max (ρ = −0.47, p = 0.015) after 12 weeks of exercise and positively to amounts of intraperitoneal fat (ρ = 0.40, p = 0.044) and liver fat (ρ = 0.58, p = 0.01). However, circulating BCAAs and related metabolites did not respond to 12 weeks of exercise, with the exception of isoleucine, which increased in normoglycaemic men (10 μmol/l, p = 0.01). Pathway analyses of mRNA-sequencing data implied reduced BCAA catabolism in both SkM and ScWAT in men with dysglycaemia compared with men with normoglycaemia at baseline. Gene expression levels related to BCAA metabolism correlated positively with GIR and markers of mitochondrial content in both SkM and ScWAT, and negatively with fat mass generally, and particularly with intraperitoneal fat mass. mRNA-sequencing pathway analysis also implied increased BCAA metabolism after 12 weeks of exercise in both groups and in both tissues, including enhanced expression of the gene encoding branched-chain α-ketoacid dehydrogenase (BCKDH) and reduced expression of the BCKDH phosphatase in both groups and tissues. Gene expression of SLC25A44, which encodes a mitochondrial BCAA transporter, was increased in SkM in both groups, and gene expression of BCKDK, which encodes BCKDH kinase, was reduced in ScWAT in dysglycaemic men. Mediation analyses indicated a pronounced effect of enhanced SkM (~53%, p = 0.022), and a moderate effect of enhanced ScWAT (~18%, p = 0.018) BCAA metabolism on improved insulin sensitivity after 12 weeks of exercise, based on mRNA sequencing. In comparison, plasma concentration of BCAAs did not mediate any effect in this regard. Conclusion/interpretation Plasma BCAA concentration was largely unresponsive to long-term exercise and unrelated to exercise-induced insulin sensitivity. On the other hand, the insulin-sensitising effect of long-term exercise in men may be explained by enhanced SkM and, to a lesser degree, also by enhanced ScWAT BCAA catabolism.

scholarly journals Host Gene Expression Kinetics During Treatment of Tuberculosis in HIV-Coinfected Individuals Is Independent of Highly Active Antiretroviral Therapy

2018 ◽  
Vol 218 (11) ◽  
pp. 1833-1846 ◽  
Author(s):  
Gebremedhin Gebremicael ◽  
Desta Kassa ◽  
Edwin Quinten ◽  
Yodit Alemayehu ◽  
Atsbeha Gebreegziaxier ◽  
...  
Keyword(s):  
Gene Expression ◽  
Antiretroviral Therapy ◽  
Highly Active Antiretroviral Therapy ◽  
Host Gene ◽  
Host Gene Expression ◽  
Highly Active ◽  
Expression Kinetics

scholarly journals Cellular Mechanism Underlying Highly-Active or Antiretroviral Therapy-Induced Lipodystrophy: Atazanavir, a Protease Inhibitor, Compromises Adipogenic Conversion of Adipose-Derived Stem/Progenitor Cells through Accelerating ER Stress-Mediated Cell Death in Differentiating Adipocytes

2021 ◽  
Vol 22 (4) ◽  
pp. 2114
Author(s):  
Sadanori Akita ◽  
Keiji Suzuki ◽  
Hiroshi Yoshimoto ◽  
Akira Ohtsuru ◽  
Akiyoshi Hirano ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Antiretroviral Therapy ◽  
Protease Inhibitor ◽  
Er Stress ◽  
Highly Active Antiretroviral Therapy ◽  
Adipogenic Differentiation ◽  
Cell Lineage ◽  
Protein S ◽  
Altered Expression ◽  
Highly Active

Lipodystrophy is a common complication in human immunodeficiency virus (HIV)-infected patients receiving highly active antiretroviral therapy (HAART) or antiretroviral therapy (ART). Previous studies demonstrated that endoplasmic reticulum (ER) stress-mediated unfolded protein response (UPR) is involved in lipodystrophy; however, the detailed mechanism has not been fully described in human adipogenic cell lineage. We utilized adipose tissue-derived stem cells (ADSCs) obtained from human subcutaneous adipose tissue, and atazanavir (ATV), a protease inhibitor (PI), was administered to ADSCs and ADSCs undergoing adipogenic conversion. Marked repression of adipogenic differentiation was observed when ATV was administered during 10 days of ADSC culture in adipogenic differentiation medium. Although ATV had no effect on ADSCs, it significantly induced apoptosis in differentiating adipocytes. ATV treatment also caused the punctate appearance of CCAAT-enhancer-binding (C/EBP) protein homologous protein (CHOP), and altered expression of CHOP and GRP78/Bip, which are the representation of ER stress, only in differentiating adipocytes. Administration of UPR inhibitors restored adipogenic differentiation, indicating that ER stress-mediated UPR was induced in differentiating adipocytes in the presence of ATV. We also observed autophagy, which was potentiated in differentiating adipocytes by ATV treatment. Thus, adipogenic cell atrophy leads to ATV-induced lipodystrophy, which is mediated by ER stress-mediated UPR and accelerated autophagy, both of which would cause adipogenic apoptosis. As our study demonstrated for the first time that ADSCs are unsusceptible to ATV and its deleterious effects are limited to the differentiating adipocytes, responsible target(s) for ATV-induced lipodystrophy may be protease(s) processing adipogenesis-specific protein(s).

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