• Bibliometric
• Citation analysis
• Collaboration network
• Lipodystrophy
• Lipoedema
• Liposuction

• Wnt signalling
• dermal adipocytes
• lipodystrophy
• skin fibrosis

• Humans
• Fibrosis
• Skin/pathology
• Lung/pathology
• Extracellular Matrix/pathology
• Fibroblasts/pathology
• Lipodystrophy/pathology
• Lipids

• R01 AR076938 NIAMS NIH HHS
• R01 AR076938 NIH HHS
• T32 AR 7505-31 NIH HHS
• T32 AR007505 NIAMS NIH HHS
• T32 AR 7569-25 NIH HHS
• T32 AR007569 NIAMS NIH HHS

• Humans
• Male
• Middle Aged
• Female
• HIV Infections/complications
• HIV Infections/drug therapy
• Cross-Sectional Studies
• Brazil/epidemiology
• Leukoplakia, Hairy

• Atrx
• Pdx1-Cre
• conditional mouse model
• endocrine dysfunction
• fatty pancreas
• hepatic stetosis
• hyperglycaemia
• inflammageing
• obesity
• pancreatic fatty replacement

• HALS (HIV-associate lypodistrophy syndrome)
• combined highly antiretroviral therapy (cART)
• metabolic disorders
• miRNA

• Antiretroviral therapy
• Cytokines
• HIV
• Immunological responders
• Inflammation
• Microbiome-immunity axis
• Microbiota
• Short chain fatty acid
• Viremia

• Cross-Sectional Studies
• Gastrointestinal Microbiome
• HIV Infections/diagnosis
• HIV Infections/drug therapy
• HIV-1
• Humans
• Microbiota
• Viremia

• HDL-C
• abdominal obesity
• age
• blood pressure
• public health

The prevalence of age-related comorbidities is increased in people living with HIV, even in those well-controlled on combination antiretroviral therapy (ART). Persistent immune activation and inflammation may play pivotal roles in the pathogenesis; however, the burden of morbidities in the older HIV infected population may be exacerbated and driven by distinct mechanisms. In a cross sectional study of 45 HIV-infected participants 60 years or older, we examined the relationships between 14 immunomodulatory and inflammatory factors and the Veterans Aging Cohort Study (VACS) Index, a metric of multimorbidity and mortality comprised of age, CD4 count, hemoglobin, Fibrosis-4 [FIB-4], and estimated glomerular filtration rate [eGFR], by linear regression analysis. All participants were virally suppressed (<50 HIV RNA copies/mL), on ART, and primarily Caucasian (86.7%), and male (91.1%). Plasma levels of monocyte/macrophage-associated (neopterin, IP-10, sCD163, sCD14, and MCP-1) and glycan-binding immunomodulatory factors (galectin (Gal)-1, Gal-3, and Gal-9) were assessed, as well as inflammatory biomarkers previously linked to the VACS Index (i.e., CRP, cystatin C, TNF-α, TNFRI, IL-6, and D-dimer) for comparison. In regression analysis, higher VACS index scores were associated with higher levels of neopterin, cystatin C, TNFRI, and Gal-9 (all p < 0.05), potentially driven by correlations found with individual VACS components, including age, CD4 count, FIB-4, and eGFR. Gal-9, cystatin C, and TNFRI directly correlated with the extent of multimorbidity. Multiple correlations among markers were observed, suggesting an interplay of overlapping, but distinct, pathways. Collectively, in addition to cystatin C and TNFRI, both galectin-9 and neopterin, independently emerged as novel fluid markers of the VACS Index and burden of comorbidity and may further guide in understanding pathogenic mechanisms of age-related disorders in older HIV-infected individuals on suppressive ART.

• HIV
• aging
• anti-retroviral therapy
• inflammation
• morbidity

People living with HIV can experience accelerated aging and the development of neurological disorders. Recently, we reported that HIV-1 infection results in a dramatic loss of peroxisomes in macrophages and brain tissue. This is significant because (i) peroxisomes are important for the innate immune response and (ii) loss of peroxisome function is associated with cellular aging and neurodegeneration. Accordingly, understanding how HIV-1 infection causes peroxisome depletion may provide clues regarding how the virus establishes persistent infections and, potentially, the development of neurological disorders. Here, we show that the accessory protein Vpu is necessary and sufficient for the induction of microRNAs that target peroxisome biogenesis factors. The ability of Vpu to downregulate peroxisome formation depends on the Wnt/β-catenin pathway. Thus, in addition to revealing a novel mechanism by which HIV-1 uses intracellular signaling pathways to target antiviral signaling platforms (peroxisomes), we have uncovered a previously unknown link between the Wnt/β-catenin pathway and peroxisome homeostasis.

Human immunodeficiency virus type 1 (HIV-1) establishes lifelong infections in humans, a process that relies on its ability to thwart innate and adaptive immune defenses of the host. Recently, we reported that HIV-1 infection results in a dramatic reduction of the cellular peroxisome pool. Peroxisomes are metabolic organelles that also function as signaling platforms in the innate immune response. Here, we show that the HIV-1 accessory protein Vpu is necessary and sufficient for the depletion of cellular peroxisomes during infection. Vpu induces the expression of four microRNAs that target mRNAs encoding proteins required for peroxisome formation and metabolic function. The ability of Vpu to downregulate peroxisomes was found to be dependent upon the Wnt/β-catenin signaling pathway. Given the importance of peroxisomes in innate immune signaling and central nervous system function, the roles of Vpu in dampening antiviral signaling appear to be more diverse than previously realized. Finally, our findings highlight a potential role for Wnt/β-catenin signaling in peroxisome homeostasis through modulating the production of biogenesis factors.

• HIV
• Vpu
• miRNAs
• peroxisomes
• β-catenin

• Adipose tissue
• HIV
• antiretroviral treatment
• diabetes
• dyslipidemia
• insulin resistance
• integrase inhibitors
• non-nucleoside analogues reverse transcriptase inhibitors
• nucleoside analogues reverse transcriptase inhibitors
• protease inhibitors
• steatosis

Obesity, type 2 diabetes mellitus (T2DM) and aging are associated with pancreatic cancer risk, but the mechanisms of pancreatic cancer development caused by these factors are not clearly understood. Syrian golden hamsters are susceptible to N‐nitrosobis(2‐oxopropyl)amine (BOP)‐induced pancreatic carcinogenesis. Aging, BOP treatment and/or a high‐fat diet cause severe and scattered fatty infiltration (FI) of the pancreas with abnormal adipokine production and promote pancreatic ductal adenocarcinoma (PDAC) development. The KK‐A^y mouse, a T2DM model, also develops severe and scattered FI of the pancreas. Treatment with BOP induced significantly higher cell proliferation in the pancreatic ducts of KK‐A^y mice, but not in those of ICR and C57BL/6J mice, both of which are characterized by an absence of scattered FI. Thus, we hypothesized that severely scattered FI may be involved in the susceptibility to PDAC development. Indeed, severe pancreatic FI, or fatty pancreas, is observed in humans and is associated with age, body mass index (BMI) and DM, which are risk factors for pancreatic cancer. We analyzed the degree of FI in the non‐cancerous parts of PDAC and non‐PDAC patients who had undergone pancreatoduodenectomy by histopathology and demonstrated that the degree of pancreatic FI in PDAC cases is significantly higher than that in non‐PDAC controls. Moreover, the association with PDAC is positive, even after adjusting for BMI and the prevalence of DM. Accumulating evidence suggests that pancreatic FI is involved in PDAC development in animals and humans, and further investigations to clarify the genetic and environmental factors that cause pancreatic FI are warranted.

• cancer susceptibility
• fatty infiltration
• obesity
• pancreatic cancer
• type 2 diabetes mellitus

• Adipocytes
• Adipose stem cells
• Insulin
• Obesity
• Thermogenesis
• Uncoupling protein

Interleukin (IL)-18 is involved in regulation of lipid and glucose metabolism. Mice lacking whole-body IL-18 signalling are prone to develop weight gain and insulin resistance, a phenotype which is associated with impaired fat oxidation and ectopic skeletal muscle lipid deposition. IL-18 mRNA is expressed in human skeletal muscle but a role for IL-18 in muscle has not been identified. Patients with HIV-infection and lipodystrophy (LD) are characterized by lipid and glucose disturbances and increased levels of circulating IL-18. We hypothesized that skeletal muscle IL-18 and IL-18 receptor (R) expression would be altered in patients with HIV-lipodystrophy.

Twenty-three HIV-infected patients with LD and 15 age-matched healthy controls were included in a cross-sectional study. Biopsies from the vastus lateralis muscle were obtained and IL-18 and IL-18R mRNA expression were measured by real-time PCR and sphingolipids (ceramides, sphingosine, sphingosine-1-Phosphate, sphinganine) were measured by HPLC. Insulin resistance was assessed by HOMA and the insulin response during an OGTT.

Patients with HIV-LD had a 60% and 54% lower level of muscular IL-18 and IL-18R mRNA expression, respectively, compared to age-matched healthy controls. Patients with HIV-LD had a trend towards increased levels of ceramide (18.3±4.7 versus 14.8±3.0,p = 0.06) and sphingosine (0.41±0.13 versus 0.32±0.07, and lower level of sphinganine (p = 0.06). Low levels of muscle IL-18 mRNA correlated to high levels of ceramides (r = -0.31, p = 0.038) and sphingosine-1P (r = -0.29, p = 0.046) in skeletal muscle, whereas such a correlation was not found in healthy controls. Low expression of IL-18 mRNA in skeletal muscle correlated to elevated concentration of circulating triglycerides (R_p = -0.73, p<0.0001). Neither muscle expression of IL-18 mRNA or ceramide correlated to parameters of insulin resistance.

IL-18 (mRNA) in skeletal muscle appears to be involved in the regulation of intramuscular lipid metabolism and hypertriglyceridemia.

• Adult
• HIV Infections/complications
• HIV Infections/metabolism
• Humans
• Interleukin-18/metabolism
• Lipid Metabolism
• Lipodystrophy/complications
• Lipodystrophy/metabolism
• Male
• Middle Aged
• Muscle, Skeletal/metabolism
• Receptors, Interleukin-18/metabolism

HIV-associated lipodystrophy syndrome (HALS) is characterized by body fat redistribution as a consequence of the antiretroviral therapy (ART) introduction, associated with an increased risk of cardiovascular disease development. Subjective diagnosis, classified between three subtypes according to the body region on which fat is lost and/or accumulated, named lipoatrophy, lipohypertrophy, and mixed lipodystrophy, is possibly accompanied with metabolic alterations. Forty people living with HIV/AIDS (PLHA), with clinical diagnosis of HALS and from both genders, were assessed. They performed ambulatorial follow-up and used ART regularly. The main findings were greater lipid profile alterations among women, while no metabolic profile differences were found between the HALS subtypes. The lipohypertrophy group showed major alterations, with higher values for total body fat percent, visceral fat area (VFA), body mass index (BMI), and abdominal and neck circumferences when compared to the other groups. Lean body mass was superior only compared to the mixed lipodystrophy group, and fat mass only compared to the lipoatrophy group. BMI showed strong correlation with the VFA. In conclusion, despite anthropometric alterations related to HALS these individuals present, those are not accompanied with metabolic alterations. Strategies, as behavioral changes and disorders prevention, are important to decrease the risk of cardiovascular disease development.

• Antiretroviral therapy
• Cardiovascular risk
• HIV infection
• Hypertension
• Metabolic syndrome

• Aged
• Aging/physiology
• Comorbidity
• Disease Management
• HIV Infections/epidemiology
• Humans
• Hypertension/epidemiology
• Hypertension/metabolism
• Hypertension/therapy
• Metabolic Syndrome/epidemiology
• Risk Factors

• K01 TW010281 FIC NIH HHS

• Fat redistribution
• Lipoatrophy
• Lipohypertrophy
• Treatment adherance

• Adipose tissue
• Body fat distribution
• Development
• Transcription factor

• Adipokines/metabolism
• Adipose Tissue, Brown/embryology
• Adipose Tissue, Brown/growth & development
• Adipose Tissue, Brown/metabolism
• Adipose Tissue, White/embryology
• Adipose Tissue, White/growth & development
• Adipose Tissue, White/metabolism
• Adiposity
• Animals
• Energy Metabolism
• Gene Expression Regulation, Developmental
• Humans
• Lipogenesis
• Lipolysis
• Morphogenesis
• Signal Transduction
• Transcription Factors/genetics
• Transcription Factors/metabolism

• G1001959 Medical Research Council

• CYP3A4
• ER stress
• PXR
• STAT3
• proinflammatory cytokines

• Congenital lipodystrophy
• HIV-associated lipodystrophy
• Leptin
• Metabolism

• Animals
• HIV-Associated Lipodystrophy Syndrome/drug therapy
• HIV-Associated Lipodystrophy Syndrome/metabolism
• Humans
• Leptin/metabolism
• Leptin/pharmacology
• Lipodystrophy/drug therapy
• Lipodystrophy/metabolism
• Metabolic Diseases/drug therapy
• Metabolic Diseases/metabolism

• Adiponectin
• HAART
• HALS
• HIV
• HIV/HAART-associated lipodystrophy syndrome
• IGF-1
• IL-6
• Leptin
• Lipodystrophy
• PPAR-gamma
• TNF-α
• highly active antiretroviral therapy
• insulin-like growth factor 1
• interleukin-6
• peroxisome proliferator-activated receptor-gamma
• tumor necrosis factor-alpha

• Adiponectin/physiology
• Adiponectin/therapeutic use
• Glucose Intolerance/drug therapy
• HIV-Associated Lipodystrophy Syndrome/drug therapy
• HIV-Associated Lipodystrophy Syndrome/etiology
• Humans
• Leptin/physiology
• Leptin/therapeutic use
• Metformin/therapeutic use
• Thiazolidinediones/therapeutic use

Highly active antiretroviral therapy (HAART) has considerably improved the prognosis of HIV-infected patients. However, prolonged use of HAART has been related to long-term adverse events that can compromise patient health such as HIV-associated lipodystrophy syndrome (HALS) and nonalcoholic fatty liver disease (NAFLD). There is consistent evidence for a central role of mitochondrial dysfunction in these pathologies. Nucleotide reverse transcriptase inhibitors (NRTIs) have been described to be mainly responsible for mitochondrial dysfunction in adipose tissue and liver although nonnucleoside transcriptase inhibitors (NNRTIs) or protease inhibitors (PIs) have also showed mitochondrial toxicity, which is a major concern for the selection and the long-term adherence to a particular therapy. Several mechanisms explain these deleterious effects of HAART on mitochondria, and evidence points to other mechanisms beyond the “Pol-γ hypothesis.” HIV infection has also direct effects on mitochondria. In addition to the negative effects described for HIV itself and/or HAART on mitochondria, HIV-infected patients are more prone to develop a premature aging and, therefore, to present an increased oxidative state that could lead to the development of these metabolic disturbances observed in HIV-infected patients.

• Antiretroviral therapy, highly active
• Glucose metabolism
• HIV
• Leptin
• Lipodystrophy

• Adult
• Antigens, CD/biosynthesis
• Antigens, Differentiation, Myelomonocytic/biosynthesis
• Antiretroviral Therapy, Highly Active/adverse effects
• Back
• Body Composition
• DNA, Mitochondrial/genetics
• Female
• HIV-Associated Lipodystrophy Syndrome/chemically induced
• HIV-Associated Lipodystrophy Syndrome/pathology
• Humans
• Lipodystrophy
• Male
• Middle Aged
• Oligonucleotide Array Sequence Analysis
• Subcutaneous Fat/pathology
• Subcutaneous Fat, Abdominal/pathology

• Anti-HIV Agents/adverse effects
• Anti-HIV Agents/therapeutic use
• Antiretroviral Therapy, Highly Active/adverse effects
• HIV Infections/drug therapy
• HIV Infections/metabolism
• Humans
• Insulin Resistance

• AI091492-01 NIAID NIH HHS