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Autoantibodies to Perilipin-1 Define a Subset of Acquired Generalized Lipodystrophy.

ABSTRACT: Acquired lipodystrophy is often characterized as an idiopathic subtype of lipodystrophy. Despite suspicion of an immune-mediated pathology, biomarkers such as autoantibodies are generally lacking. Here, we used an unbiased proteome-wide screening approach to identify autoantibodies to the adipocyte-specific lipid droplet protein perilipin 1 (PLIN1) in a murine model of autoimmune polyendocrine syndrome type 1 (APS1). We then tested for PLIN1 autoantibodies in human subjects with acquired lipodystrophy with two independent severe breaks in immune tolerance (including APS1) along with control subjects using a specific radioligand binding assay and indirect immunofluorescence on fat tissue. We identified autoantibodies to PLIN1 in these two cases, including the first reported case of APS1 with acquired lipodystrophy and a second patient who acquired lipodystrophy as an immune-related adverse event following cancer immunotherapy. Lastly, we also found PLIN1 autoantibodies to be specifically enriched in a subset of patients with acquired generalized lipodystrophy (17 of 46 [37%]), particularly those with panniculitis and other features of autoimmunity. These data lend additional support to new literature that suggests that PLIN1 autoantibodies represent a marker of acquired autoimmune lipodystrophies and further link them to a break in immune tolerance.

SUBMITTER: Mandel-Brehm C

PROVIDER: S-EPMC9797316 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Autoantibodies to Perilipin-1 Define a Subset of Acquired Generalized Lipodystrophy.

Mandel-Brehm Caleigh C Vazquez Sara E SE Liverman Christopher C Cheng Mickie M Quandt Zoe Z Kung Andrew F AF Parent Audrey A Miao Brenda B Disse Emmanuel E Cugnet-Anceau Christine C Dalle Stéphane S Orlova Elizaveta E Frolova Elena E Alba Diana D Michels Aaron A Oftedal Bergithe E BE Lionakis Michail S MS Husebye Eystein S ES Agarwal Anil K AK Li Xilong X Zhu Chengsong C Li Quan Q Oral Elif E Brown Rebecca R Anderson Mark S MS Garg Abhimanyu A DeRisi Joseph L JL

Diabetes 20230101 1

Acquired lipodystrophy is often characterized as an idiopathic subtype of lipodystrophy. Despite suspicion of an immune-mediated pathology, biomarkers such as autoantibodies are generally lacking. Here, we used an unbiased proteome-wide screening approach to identify autoantibodies to the adipocyte-specific lipid droplet protein perilipin 1 (PLIN1) in a murine model of autoimmune polyendocrine syndrome type 1 (APS1). We then tested for PLIN1 autoantibodies in human subjects with acquired lipodys ...[more]

PMID: 35709010

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Project description:ContextLipodystrophy syndromes are rare disorders of deficient adipose tissue, low leptin, and severe metabolic disease, affecting all adipose depots (generalized lipodystrophy, GLD) or only some (partial lipodystrophy, PLD). Left ventricular (LV) hypertrophy is common (especially in GLD); mechanisms may include hyperglycemia, dyslipidemia, or hyperinsulinemia.ObjectiveDetermine effects of recombinant leptin (metreleptin) on cardiac structure and function in lipodystrophy.MethodsOpen-label treatment study of 38 subjects (18 GLD, 20 PLD) at the National Institutes of Health before and after 1 (N = 27), and 3 to 5 years (N = 23) of metreleptin. Outcomes were echocardiograms, blood pressure (BP), triglycerides, A1c, and homeostasis model assessment of insulin resistance.ResultsIn GLD, metreleptin lowered triglycerides (median [interquartile range] 740 [403-1239], 138 [88-196], 211 [136-558] mg/dL at baseline, 1 year, 3-5 years, P < .0001), A1c (9.5 ± 3.0, 6.5 ± 1.6, 6.5 ± 1.9%, P < .001), and HOMA-IR (34.1 [15.2-43.5], 8.7 [2.4-16.0], 8.9 [2.1-16.4], P < .001). Only HOMA-IR improved in PLD (P < .01). Systolic BP decreased in GLD but not PLD. Metreleptin improved cardiac parameters in patients with GLD, including reduced posterior wall thickness (9.8 ± 1.7, 9.1 ± 1.3, 8.3 ± 1.7 mm, P < .01), and LV mass (140.7 ± 45.9, 128.7 ± 37.9, 110.9 ± 29.1 g, P < .01), and increased septal e' velocity (8.6 ± 1.7, 10.0 ± 2.1, 10.7 ± 2.4 cm/s, P < .01). Changes remained significant after adjustment for BP. In GLD, multivariate models suggested that reduced posterior wall thickness and LV mass index correlated with reduced triglycerides and increased septal e' velocity correlated with reduced A1c. No changes in echocardiographic parameters were seen in PLD.ConclusionMetreleptin attenuated cardiac hypertrophy and improved septal e' velocity in GLD, which may be mediated by reduced lipotoxicity and glucose toxicity. The applicability of these findings to leptin-sufficient populations remains to be determined.

Dataset Information

Autoantibodies to Perilipin-1 Define a Subset of Acquired Generalized Lipodystrophy.

Publications

Autoantibodies to Perilipin-1 Define a Subset of Acquired Generalized Lipodystrophy.

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