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SREBP1 interaction with prelamin A forms: a pathogenic mechanism for lipodystrophic laminopathies. (Articolo in rivista)
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- SREBP1 interaction with prelamin A forms: a pathogenic mechanism for lipodystrophic laminopathies. (Articolo in rivista) (literal)
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- 2008-01-01T00:00:00+01:00 (literal)
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Maraldi NM, Capanni C, Lattanzi G, Camozzi D, Facchini A, Manzoli FA. (2008)
SREBP1 interaction with prelamin A forms: a pathogenic mechanism for lipodystrophic laminopathies.
in Advances in enzyme regulation
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- Maraldi NM, Capanni C, Lattanzi G, Camozzi D, Facchini A, Manzoli FA. (literal)
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- ISI Web of Science (WOS) (literal)
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- Laboratory of Cell Biology, IOR, Bologna, Italy; IGM-C.N.R., Unit of Bologna, c/o IOR, Bologna, Italy; Laboratory of Immunology and Genetics, IOR, Bologna, Italy; Department of Human Anatomy, University of Bologna, Italy (literal)
- Titolo
- SREBP1 interaction with prelamin A forms: a pathogenic mechanism for lipodystrophic laminopathies. (literal)
- Abstract
- Mutations in the LMNA gene cause a number of distinct human diseases, collectively called laminopathies. From the phenotypic point of view, laminopathies can be divided into five classes, by considering their organ system involvement: (a) striated muscle; (b) peripheral nerves; (c) adipose tissue; (d) multiple tissue premature senescence; and (e) overlapping phenotypes with two or more tissue involvements. At the moment, 16 distinct disease phenotypes have been shown to result from more than 210 different LMNA gene mutations (Broers et al., 2006). Primary laminopathies, that is the group of diseases caused by mutations of the LMNA gene, include some major entities characterized by either specific tissue alterations, such as Emerye Dreifuss muscular dystrophy (AD-EDMD), dilated cardiomyopathy with conduction system defects (DCM-CD), limb-girdle muscular dystrophy type 1B (LGMD1B), CharcoteMarie- Tooth type 2 (CMT2B1), and familial partial lipodystrophy (FPLD), or several tissues in a systemic way, including mandibuloacral dysplasia (MADA), HutchinsoneGilford progeria syndrome (HGPS), atypical Werner syndrome, generalized lipoatrophy, insulin-resistant diabetes, leukomelanodermic papules, liver steatosis, and hypertrophic cardiomyopathy (LIRLLC), restrictive dermopathy (RD), and lethal fetal akinesia. Furthermore, numerous heterogeneous clinical situations due to mutations of the LMNA gene present overlapping phenotypes with the coexistence of two or more tissue involvements (Broers et al., 2006). FPLD phenotype, not present at birth but with onset at puberty, is characterized by absence of subcutaneous fat from extremities, whilst intra-muscular and bone marrow fat are preserved; on the other hand, excess fat deposition occurs at neck, face, back, and intra-abdominally (Garg et al., 1999). Although FPLD phenotype is more obvious in women, men are equally affected. The metabolic markers of FPLD include insulin resistance, resulting in diabetes with aging, dyslipidemia and hypertension; menstrual abnormalities, hirsutism, acanthosis nigricans are often present. The mutations found in LMNA gene, resulting in FPLD, are clustered in exons 8 and 11, encoding the globular C-terminal domain of type A lamins. The most frequent FPLD-linked LMNA mutation results in a substitution of arginine at position 482 with a neutral amino acid. The FPLD-linked LMNA missense mutations result in characteristic phenotypic alterations in a large proportion of nuclei, observed in cultured skin fibroblasts from affected subjects; these consist in abnormal shape, indented or herniated profile and increased fragility (Caron et al., 2007; Vigouroux et al., 2001). Furthermore, intranuclear aggregates, mostly localized close to the nuclear lamina, were found in R482L mutated fibroblasts (Capanni et al., 2003), which have been demonstrated to be constituted by accumulation of prelamin A (Capanni et al., 2005). Interestingly, the proportion of altered nuclei increased with the patient age and with the severity of the clinical phenotype (Caron et al., 2007). These findings opened a very intriguing question on the pathogenic role of specific LMNA mutations in FPLD as well as in other laminopathies with a lipodystrophic phenotype. In fact, the mutational hot-spot found in FPLD-linked phenotype suggests that a specific alteration in a lamin A/C region involved in the binding with transcription factors involved in adipocyte differentiation/function could result in typical lipodystrophic alterations. On the other hand, other laminopathies, including MADA, HGPS and WS, which are due to mutations not restricted to the hot-spot region found in FPLD, present lipodystrophic alterations together with insulin resistance, resulting in premature aging. Here we report experimental evidence suggesting that altered prelamin A processing is a common mechanism leading to lipodystrophy. Furthermore, we demonstrate that the resulting prelamin A accumulation reduces the rate of DNA-bound SREBP1 and lowers PPARg expression, causing impairment of pre-adipocyte differentiation. This defect, which could be considered the pathogenic mechanism of LMNA-linked lipodystrophy, can be rescued by treatment with troglitazone (TZD), a known PPARg ligand activating the adipogenic program. (literal)
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