Effects of zidovudine, stavudine and beta-aminoisobutyric acid on lipid homeostasis in mice: possible role in human fat wasting.
OBJECTIVE
Although mitochondrial DNA (mtDNA) depletion could play a role in nucleoside reverse transcriptase inhibitor-induced lipoatrophy, poor correlations between fat mtDNA levels and lipoatrophy suggest additional mechanism(s). Stavudine (d4T), zidovudine (AZT) and the thymine catabolite, beta-aminoisobutyric acid (BAIBA), but not zalcitabine (ddC) or didanosine (ddI), can increase fatty acid oxidation in liver mitochondria and plasma ketone bodies in mice. Since fat oxidation in non-adipose tissue can influence body adiposity, we sought to determine whether d4T, AZT and BAIBA can cause lipoatrophy in mice by this catabolic mechanism.


METHODS
Lean or obese ob/ob mice were treated for 6 weeks with d4T, AZT or BAIBA, and lean mice with ddC or ddI. Body fat mass was assessed by dual energy X-ray absorptiometry, and mtDNA by Slot blot hybridization in epididymal fat.


RESULTS
Whereas ddC or ddI did not change plasma beta-hydroxybutyrate and body fat mass, d4T, AZT and BAIBA increased plasma beta-hydroxybutyrate in lean mice suggesting increased hepatic fatty acid oxidation and ketogenesis. Despite unchanged food consumption, a supra-pharmacological dose of d4T tended to decrease, whilst AZT and BAIBA decreased body fat mass. Fat mtDNA and plasma triglycerides, cholesterol, glucose, insulin, leptin and adiponectin levels were unchanged. In obese mice, d4T, AZT and BAIBA did not increase plasma beta-hydroxybutyrate, and only AZT decreased body fat mass without reducing fat mtDNA.


CONCLUSIONS
d4T and AZT can enhance hepatic fat oxidation and cause fat wasting, without decreasing adipose tissue mtDNA and without causing insulin resistance in mice. BAIBA, a thymine catabolite, reproduces these effects. These catabolic effects could play a role in the lipoatrophy, which can occur in AZT- or d4T-treated patients.
Maisonneuve
Caroline
C
INSERM Unité 481, Faculté de Médecine Xavier Bichat, Paris, France.
Igoudjil
Anissa
A
Begriche
Karima
K
Lettéron
Philippe
P
Guimont
Marie-Christine
MC
Bastin
Jean
J
Laigneau
Jean-Pierre
JP
Pessayre
Dominique
D
Fromenty
Bernard
B
D000621:Aminoisobutyric Acids / Q000009:adverse effects* / Q000097:blood; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects*; D001835:Body Weight; D006706:Homeostasis; D050356:Lipid Metabolism; D008060:Lipodystrophy / Q000139:chemically induced*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D018119:Stavudine / Q000008:administration & dosage / Q000009:adverse effects*; D013851:Thinness; D015215:Zidovudine / Q000008:administration & dosage / Q000009:adverse effects*
D000621:Aminoisobutyric Acids; D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D018119:Stavudine; C033435:3-aminoisobutyric acid