Impaired adipogenic capacity in induced pluripotent stem cells from lipodystrophic patients with BSCL2 mutations

Mori, Eigo; Fujikura, Junji; Noguchi, Michio; Nakao, Kazuhiro; Matsubara, Masaki; Sone, Masakatsu; Taura, Daisuke; Kusakabe, Toru; Tanaka, Takayuki; Hosoda, Kiminori; Takahashi, Kazutoshi; Asaka, Isao; Inagaki, Nobuya; Nakao, Kazuwa

doi:10.1016/j.metabol.2015.12.015

Cited by 25 publications

(19 citation statements)

References 57 publications

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“…In the same way, this is strictly related to a decrease in TG synthesis ( Figure 4(b) ). Researchers observed a reduction in LD formation, associated with impaired lipid accumulation capacity during adipogenic differentiation of fibroblasts in patients with mutations E189X and R275X in seipin [ 67 ]. Moreover, other studies showed a reduction of almost 50% in TG content during differentiation of 3T3-L1 mouse preadipocyte stem cells carrying the A212P mutation.…”

Section: Seipin Loss-of-functionmentioning

confidence: 99%

Exploring Seipin: From Biochemistry to Bioinformatics Predictions

Sarmento

Medeiros

Agnez-Lima

et al. 2018

International Journal of Cell Biology

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Seipin is a nonenzymatic protein encoded by the BSCL2 gene. It is involved in lipodystrophy and seipinopathy diseases. Named in 2001, all seipin functions are still far from being understood. Therefore, we reviewed much of the research, trying to find a pattern that could explain commonly observed features of seipin expression disorders. Likewise, this review shows how this protein seems to have tissue-specific functions. In an integrative view, we conclude by proposing a theoretical model to explain how seipin might be involved in the triacylglycerol synthesis pathway.

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Section: Seipin Loss-of-functionmentioning

confidence: 99%

Exploring Seipin: From Biochemistry to Bioinformatics Predictions

Sarmento

Medeiros

Agnez-Lima

et al. 2018

International Journal of Cell Biology

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“…BSCL2 is the causative gene for SPG17. This mutation is deleterious [26], and we suggest that this nonsense mutation is implicated in phenotype differences between two cases: leg spasticity of III-3 is stronger than that of III-1.…”

Section: Hsp Due To Lyst Mutationmentioning

confidence: 76%

Lysosomal Dysfunctions in Hereditary Spastic Paraplegias

Shimazaki¹

2017

Lysosomes - Associated Diseases and Methods to Study Their Function

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Hereditary spastic paraplegias (HSPs) comprise a heterogeneous group of inherited neurodegenerative diseases with the cardinal feature of a length-dependent degeneration of corticospinal motor axons. They are classified by their mapped genetic loci, SPG1-SPG78. Recently, lysosomal dysfunction is one of the pathomechanism for some autosomalrecessive HSPs. SPG11 is caused by loss-of-function mutations in the SPG11 gene. Its gene product is called spatacsin, which is needed for the recycling of lysosomes from autolysosomes. SPG15 is caused by loss-of-function mutation in the ZFYVE26 gene. The ZFYVE26 gene encodes spastizin. Mutations in spastizin impair autophagosome maturation and lead to an accumulation of immature autophagosomes. SPG48/KIAA0415 encodes AP5Z1, known to be a spatacsin and spastizin interactor. Its mutations lead to loss of protein or mutated forms of protein with defective autophagy. The TECPR2 is a human ATG8-binding protein and positive regulator of autophagy, which plays a key role in major adult and pediatric neurodegenerative diseases. Mutations in the lysosomal trafficking regulator (LYST) gene have been reported to cause hereditary spastic paraplegia. The LYST protein is involved in control of the exocytosis of secretory lysosomes. Recently, Drosophila with a gene mutation of an LYST homolog was revealed to exhibit impaired autophagy.

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“…In addition to GPATs, AGPAT2 and lipins, a range of other proteins have been identified as seipin interacting partners that may regulate lipid droplets in multiple cell types and species. These include ADRP, SERCA2A, 14-3-3β, perilipin, promethin and Reep1 in mammalian cells [17][18][19][36][37][38][39][40][41] and Pet10p, Ldo45 and Ldo16 in yeast [42][43][44] . In addition, two groups have recently reported the structure of seipin homo-oligomers determined by cryo-EM.…”

Section: Discussionmentioning

confidence: 99%

Oligomers of the lipodystrophy protein seipin may co-ordinate GPAT3 and AGPAT2 enzymes to facilitate adipocyte differentiation

Sim

Persiani

Talukder

et al. 2020

Sci Rep

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Seipin deficiency causes severe congenital generalized lipodystrophy (CGL) and metabolic disease. However, how seipin regulates adipocyte development and function remains incompletely understood. We previously showed that seipin acts as a scaffold protein for AGPAT2, whose disruption also causes CGL. More recently, seipin has been reported to promote adipogenesis by directly inhibiting GPAT3, leading to the suggestion that GPAT inhibitors could offer novel treatments for CGL. Here we investigated the interactions between seipin, GPAT3 and AGPAT2. We reveal that seipin and GPAT3 associate via direct interaction and that seipin can simultaneously bind GPAT3 and AGPAT2. Inhibiting the expression of seipin, AGPAT2 or GPAT3 led to impaired induction of early markers of adipocyte differentiation in cultured cells. However, consistent with normal adipose mass in GPAT3null mice, GPAT3 inhibition did not prevent the formation of mature adipocytes. Nonetheless, loss of GPAT3 in seipin-deficient preadipocytes exacerbated the failure of adipogenesis in these cells. Thus, our data indicate that GPAT3 plays a modest positive role in adipogenesis and argue against the potential of GPAT inhibitors to rescue white adipose tissue mass in CGL2. Overall, our study reveals novel mechanistic insights regarding the molecular pathogenesis of severe lipodystrophy caused by mutations in either seipin or AGPAT2.

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Impaired adipogenic capacity in induced pluripotent stem cells from lipodystrophic patients with BSCL2 mutations

Cited by 25 publications

References 57 publications

Exploring Seipin: From Biochemistry to Bioinformatics Predictions

Exploring Seipin: From Biochemistry to Bioinformatics Predictions

Lysosomal Dysfunctions in Hereditary Spastic Paraplegias

Oligomers of the lipodystrophy protein seipin may co-ordinate GPAT3 and AGPAT2 enzymes to facilitate adipocyte differentiation

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