First molecular biomarker for acquired generalized lipodystrophy discovered

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Researchers at UT Southwestern Medical Center have discovered the first molecular biomarker for acquired generalized lipodystrophy (AGL), a rare disorder in which fat deposits are destroyed, causing patients to have dangerously low body fat, signs of accelerated aging, and severe metabolic diseases including diabetes and fatty liver. The findings, published in Diabetes, could help diagnose patients more quickly and unlock new therapies for those with AGL.

The discovery of this autoantibody provides a new diagnostic tool for AGL patients and could potentially result in novel therapeutic options."

Abhimanyu Garg, M.D., Professor of Internal Medicine, Section Chief of Nutrition and Metabolic Diseases in the Division of Endocrinology, and Director of Metabolic Diseases in UT Southwestern's Center for Human Nutrition

Dr. Garg was one of three senior authors of the study, conducted in collaboration with colleagues at the University of California, San Francisco, and institutions in France, Norway, and Russia.

The underlying cause of AGL, which is most often diagnosed in children but also can appear in adults, has so far remained unclear. Approximately 100 cases have been reported worldwide, making it difficult to study the commonalities among patients. For years, researchers have suspected the disorder is an autoimmune condition, in which a person's immune system attacks the body. However, they had been unable to pinpoint any unusual or unique autoantibodies in AGL patients.

Dr. Garg and his colleagues utilized their UT Southwestern biorepository containing blood, DNA, and clinical data collected from 46 patients with AGL over the past 30 years.

"We now have the largest collection of data on AGL patients in the world," Dr. Garg said. "The banked samples from these patients were key to our new discovery."

The team sought to detect antibodies against nearly 19,500 different human proteins in the blood samples from the patients and healthy controls, homing in on the perilipin-1 autoantibody as the key finding differentiating people with AGL from those without the disease. Perilipin-1 is a protein known to play a role in the storage of fat molecules in fat cells. The autoantibody was found to be present in 17 of the 46 patients but in none of the controls.

The researchers concluded that the perilipin-1 autoantibody – which would direct the immune system to attack the protein and therefore harm fat cells – might play a role in AGL.

More detailed profiling of the patients whose blood contained the perilipin-1 autoantibody showed that those with one subtype of AGL, known as AGL with panniculitis, were even more likely to have them. Panniculitis is a process whereby immune cells infiltrate fat tissue, causing destruction and death of fat cells. The researchers also found that laboratory mice known to develop AGL-like disease also had the autoantibody to perilipin-1.

Further work is needed to understand the prevalence of the perilipin-1 autoantibody among patients with AGL and related disorders, as well as whether an immunotherapy drug or procedure could remove or block the autoantibody to treat those developing AGL.

Other UTSW researchers who contributed to this study include Anil K. Agarwal, Xilong Li, and Chengsong Zhu.

Dr. Garg holds a Distinguished Chair in Human Nutrition Research.

The research was supported by funding from the National Institutes of Health (R01-DK105448) and the Southwestern Medical Foundation.

Source:
Journal reference:

Mandel-Brehm, C., et al. (2023) Autoantibodies to Perilipin-1 Define a Subset of Acquired Generalized Lipodystrophy. Diabetes. doi.org/10.2337/db21-1172.

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