Acquired
generalized lipodystrophy (AGL) is a rare condition characterized by massive loss of adipose tissue through the body, causing severe metabolic complications. Autoimmune destruction of adipocytes is strongly suspected based on the frequent association of AGL with autoimmune disorders. In 2018,
autoantibodies against
perilipin 1 (PLIN1) were identified in three patients with autoimmune-associated AGL. However, the pathogenic mechanism and clinical impact of anti-PLIN1 remain unsolved. The prevalence of anti-PLIN1
autoantibodies in an AGL cohort of 40 patients was 50% (20 of 40). Among positive patients, 10 had the autoimmune variety and 10 had
panniculitis-associated AGL. The
IgG isotype was predominant, although some
IgM antibodies were detected.
Epitope-mapping studies did not identify a single, major
epitope. Instead,
autoantibodies typically bound to several different
peptides, among which the central (233-405) domain was detected in all antibody-positive patients, for both
IgG and
IgM autoantibodies. In-depth
epitope mapping indicated that anti-PLIN1
autoantibodies predominantly recognize the αβ-
hydrolase domain containing 5 (ABHD5) binding site (383-405).
Autoantibodies dose-dependently blocked the binding of PLIN1 to ABHD5 and caused a dislocation of ABHD5 toward the cytosol, leading to an increase in lipolysis and
lipase activities. Finally, anti-PLIN1 titers significantly correlated with the amount of fat loss, metabolic control impairment, and severity of liver injury. Our data strongly support that anti-PLIN1
autoantibodies are a diagnostic
biomarker and a cause of
lipodystrophy in patients with AGL.