Maraldi Nadir M, Capanni Cristina, Mattioli Elisabetta, Columbaro Marta, Squarzoni Stefano, Parnaik Weena K, Wehnert Manfred, Lattanzi Giovanna
Department of Human Anatomy, University of Bologna, Italy.
Acta Biomed. 2007;78 Suppl 1:207-15.
The understanding of a common complex phenotype such as insulin resistance can be favoured by evaluation of monogenic syndromes. Clinical definition, pathogenesis, and therapeutical strategies for the insulin resistance syndrome can thus be improved by the characterization at the molecular genetic level of monogenic forms of lipodystrophies. Here we report experimental evidence on the pathogenic mechanism underlying insulin resistance in a rare form of laminopathy, due to mutation of the LMNA gene coding for lamin A/C, the Dunnigan-type familial partial lipodystrophy (FPLD). The defect, consisting in the intranuclear accumulation of mutant unprocessed precursors of lamin A, reduces the amount of the DNA-bound adipocyte transcription factor sterol regulatory element binding protein 1 (SREBP1) and lowers the peroxisome proliferator-activated receptor (PPARgamma) expression, causing the impairment of pre-adipocyte differentiation. The treatment with the PPARgamma ligand troglitazone (TDZ) is able to rescue the adipogenic program. Since FPLD recapitulates the essential metabolic abnormalities of the common insulin resistance syndrome, the beneficial effects of TDZ on monogenic lipodystrophies might provide a clue as to the future treatment strategies also for the common syndrome of insulin resistance.
对单基因综合征的评估有助于理解胰岛素抵抗等常见复杂表型。因此，通过对单基因形式脂肪营养不良进行分子遗传学特征分析，可以改进胰岛素抵抗综合征的临床定义、发病机制和治疗策略。在此，我们报告了一种罕见的核纤层蛋白病（由编码核纤层蛋白A/C的LMNA基因突变引起，即邓尼根型家族性部分脂肪营养不良，FPLD）中胰岛素抵抗潜在致病机制的实验证据。该缺陷表现为突变的未加工核纤层蛋白A前体在细胞核内积累，减少了与DNA结合的脂肪细胞转录因子固醇调节元件结合蛋白1（SREBP1）的量，并降低了过氧化物酶体增殖物激活受体（PPARγ）的表达，导致前脂肪细胞分化受损。用PPARγ配体曲格列酮（TDZ）治疗能够挽救脂肪生成程序。由于FPLD概括了常见胰岛素抵抗综合征的基本代谢异常，TDZ对单基因脂肪营养不良的有益作用可能为常见胰岛素抵抗综合征的未来治疗策略提供线索。
