Association between altered expression of adipogenic factor SREBP1 in lipoatrophic adipose tissue from HIV-1-infected patients and abnormal adipocyte differentiation and insulin resistance.
BACKGROUND
Lipodystrophy is a major side-effect of antiretroviral therapy but its pathophysiology remains elusive. In-vitro studies show that HIV-1-protease inhibitors affect adipocyte differentiation at an early step involving sterol-regulatory-element-binding-protein-1 (SREBP1), but in-vivo studies are lacking.


METHODS
We compared fat morphology and mRNA and protein expression of major adipocyte differentiation markers and cytokines in subcutaneous abdominal adipose tissue from 26 HIV-1-infected patients who developed peripheral lipoatrophy while on protease inhibitors and from 18 HIV-1-seronegative healthy controls.


RESULTS
Patients' fat contained a higher proportion of small adipocytes than control fat, together with lower mRNA concentrations of the adipogenic differentiation factors CCAAT-enhancer binding protein (C/EBP) beta and alpha, peroxisome proliferator-activated receptor (PPAR) gamma, and the 1c isoform of SREBP1, with a median decrease of 93% in the latter. The SREBP1 protein concentration was increased 2.6-fold, whereas the PPARgamma protein concentration was decreased by 70%. The expression of adipocyte-specific markers, including leptin, was lower in fat from patients than in fat from controls, whereas expression of tumour necrosis factor (TNF) alpha was higher and correlated negatively with the expression of SREBP1c and downstream adipogenic factors. SREBP1c mRNA concentrations correlated negatively, and TNFalpha mRNA concentrations positively, with glycaemia and insulin resistance, but did not correlate with lipid variables.


CONCLUSIONS
The altered differentiation status of peripheral adipocytes in HIV-1-infected patients with antiretroviral-induced lipoatrophy is associated with greatly reduced SREBP1c expression. Since the differentiation factor SREBP1 is rapidly targeted by protease inhibitors in vitro, our results suggest that SREBP1c could be an important mediator of peripheral lipoatrophy in this setting, leading to metabolic alterations such as insulin resistance.
Bastard
Jean Philippe
JP
INSERM Research Unit 402, Faculty of Medicine Saint-Antoine, Paris, France.
Caron
Martine
M
Vidal
Hubert
H
Jan
Véronique
V
Auclair
Martine
M
Vigouroux
Corinne
C
Luboinski
Jacqueline
J
Laville
Martine
M
Maachi
Mustapha
M
Girard
Pierre Marie
PM
Rozenbaum
Willy
W
Levan
Philippe
P
Capeau
Jacqueline
J
D017667:Adipocytes / Q000473:pathology*; D000273:Adipose Tissue / Q000378:metabolism*; D000328:Adult; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000032:analysis; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000032:analysis; D022762:CCAAT-Enhancer-Binding Proteins / Q000032:analysis* / Q000235:genetics; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000032:analysis* / Q000235:genetics; D005260:Female; D015658:HIV Infections / Q000150:complications* / Q000188:drug therapy* / Q000473:pathology*; D015497:HIV-1; D006801:Humans; D007333:Insulin Resistance; D020738:Leptin / Q000032:analysis; D008060:Lipodystrophy / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D011480:Protease Inhibitors / Q000009:adverse effects*; D012333:RNA, Messenger / Q000032:analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000032:analysis; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D022763:CCAAT-Enhancer-Binding Protein-alpha; D022782:CCAAT-Enhancer-Binding Protein-beta; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D020738:Leptin; D011480:Protease Inhibitors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha