SMP30 deficiency in mice causes an accumulation of neutral lipids and phospholipids in the liver and shortens the life span

Ishigami, Akihito; Kondo, Yoshitaka; Nanba, Reiko; Ohsawa, Tomonori; Handa, Shizuo; Kubo, Sachiho; Akita, Masumi; Maruyama, Naoki

doi:10.1016/j.bbrc.2004.01.091

Cited by 100 publications

(84 citation statements)

References 25 publications

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“…A similar change was reported in ODS (osteogenic disorder Shionogi) rats that survived for a long time on a vitamin C-deficient diet (17). However, never before did we observe scurvy symptoms in the knockout mice that were fed autoclaved mouse chow, despite their smaller body size and shorter life span (3,4). Assuming that an average weight of mice is 25 g and that the amount of chow taken per day is 4 g (18), SMP30 knockout mice ingest Ͻ0.01 mg͞g of body weight per day.…”

Section: Discussionmentioning

confidence: 97%

“…To examine the physiological function of SMP30, we established SMP30 knockout mice (3) and found that they were viable and fertile, although they were lower in body weight and shorter in life span than WT mice (4). Their livers were also far more susceptible to TNF-␣-and Fas-mediated apoptosis than those of WT mice, indicating that SMP30 may act to protect cells from apoptosis (3).…”

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confidence: 99%

“…Their livers were also far more susceptible to TNF-␣-and Fas-mediated apoptosis than those of WT mice, indicating that SMP30 may act to protect cells from apoptosis (3). The livers of SMP30 knockout mice showed abnormal accumulations of triglycerides, cholesterol, and phospholipids (4). In addition, the lungs of these knockout mice had enlarged alveolar airspaces during their first to sixth month of life (2).…”

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confidence: 99%

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Senescence marker protein 30 functions as gluconolactonase in l -ascorbic acid biosynthesis, and its knockout mice are prone to scurvy

Kondo

Inai

Sato

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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215

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We originally identified senescence marker protein 30 (SMP30) as a distinctive protein whose expression decreases in an androgenindependent manner with aging. Here, we report its sequence homology found in two kinds of bacterial gluconolactonases (GNLs) by using the BLAST search. Then, through a biochemical study, we identify SMP30 as the lactone-hydrolyzing enzyme GNL of animal species. SMP30 purified from the rat liver had lactonase activity toward various aldonolactones, such as D-and L-glucono-␦-lactone, D-and L-gulono-␥-lactone, and D-and L-galactono-␥-lactone, with a requirement for Zn 2؉ or Mn 2؉ as a cofactor. Furthermore, in SMP30 knockout mice, no GNL activity was detectable in the liver. Thus, we conclude that SMP30 is a unique GNL in the liver. The lactonase reaction with L-gulono-␥-lactone is the penultimate step in L-ascorbic acid (AA) biosynthesis, and the essential role of SMP30 in this synthetic process was verified here by a nutritional study using SMP30 knockout mice. These knockout mice (n ‫؍‬ 6), fed a vitamin C-deficient diet, did not thrive; i.e., they displayed symptoms of scurvy such as bone fracture and rachitic rosary and then died by 135 days after the start of receiving the deficient diet. The AA levels in their livers and kidneys at the time of death were <1.6% of those in WT control mice. In addition, by using the SMP30 knockout mouse, we demonstrate that the alternative pathway of AA synthesis involving D-glucurono-␥-lactone operates in vivo, although its flux is fairly small. aging ͉ osteogenic disorder ͉ vitamin C S enescence marker protein 30 (SMP30) is a 34-kDa protein whose tissue levels in the liver, kidney, and lung decrease with aging (1, 2). To examine the physiological function of SMP30, we established SMP30 knockout mice (3) and found that they were viable and fertile, although they were lower in body weight and shorter in life span than WT mice (4). Their livers were also far more susceptible to TNF-␣-and Fas-mediated apoptosis than those of WT mice, indicating that SMP30 may act to protect cells from apoptosis (3). The livers of SMP30 knockout mice showed abnormal accumulations of triglycerides, cholesterol, and phospholipids (4). In addition, the lungs of these knockout mice had enlarged alveolar airspaces during their first to sixth month of life (2). However, the molecular mechanism of SMP30 function has remained obscure.Recently, we reported that SMP30 acts as a hydrolase for diisopropyl phosphorofluoridate (5), a compound resembling chemical warfare nerve agents such as sarine, soman, and tabun. However, a physiological substrate for SMP30 must be present, because this compound is an artificial chemical. Our recent search for amino acid sequences resembling SMP30 was accomplished by using the BLAST program, which revealed that rat SMP30 is homologous with gluconolactonase (GNL) [EC 3.1.1.17], a lactone-hydrolyzing enzyme, of Nostoc punctiforme and Zymomonas mobilis (6). Therefore, we suspected that SMP30 is a GNL of animal species. In mammalian metabolism, GNL is...

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Section: Discussionmentioning

confidence: 97%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Senescence marker protein 30 functions as gluconolactonase in l -ascorbic acid biosynthesis, and its knockout mice are prone to scurvy

Kondo

Inai

Sato

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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215

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“…8) These knockout animals are viable and fertile but lower in body weight and shorter in life span than the wild-type. 9) Throughout our experiments in vitro and in vivo, the livers of SMP30 knockout mice were far more susceptible to tumor necrosis factor (TNF)-a-and Fas-mediated apoptosis than those from the wild-type. 8) Moreover, histological and biochemical analyses of livers from SMP30 knockout mice showed abnormal accumulations of neutral lipids and phospholipids.…”

mentioning

confidence: 97%

“…8) Moreover, histological and biochemical analyses of livers from SMP30 knockout mice showed abnormal accumulations of neutral lipids and phospholipids. 9) This abnormal lipid metabolism must increase the tissues' susceptibility to apoptosis. Such changes of SMP30 expression might, then, account for the deterioration of cellular functions and lowered resistance to harmful stimuli in aged tissues.…”

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confidence: 99%

Over-expression of Senescence Marker Protein-30 Decreases Reactive Oxygen Species in Human Hepatic Carcinoma Hep G2 Cells

Handa

Maruyama

Ishigami

2009

Biological & Pharmaceutical Bulletin

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Senescence Marker Protein-30 (SMP30) was originally identified as a novel protein in the rat liver, the expression of which decreases androgen-independently with aging. 1,2) SMP30 is a 34 kDa protein expressed mainly in hepatocytes and renal tubular epithelia, 1) and its amino acid sequences are highly conserved among vertebrates, i.e., 70 to 90%, strongly suggesting that the age-dependent decreases of SMP30 reported in the liver, kidney and lung may contribute to senescence.1,3-7) SMP30 transcripts have been detected in multiple mouse tissues including the liver, kidney, brain, lung and testis by reverse transcription-polymerase chain reaction (RT-PCR) analysis. 7) In humans, immunohistochemical staining has localized SMP30 mainly in parenchymal cells of the liver, proximal tubular cells of the kidney, acinal and ductal cells of the pancreas and fasciculata cells of the adrenal cortex.2) The human SMP30 gene, which is located in the p11.3-q11.2 segment of the X chromosome, 4) could be a candidate agent of X-linked diseases mapped to that region.To clarify the physiological functions and the relationships between age-associated decreases of SMP30 and disorders of aged organs, we established SMP30 knockout mice. 8) These knockout animals are viable and fertile but lower in body weight and shorter in life span than the wild-type. 9) Throughout our experiments in vitro and in vivo, the livers of SMP30 knockout mice were far more susceptible to tumor necrosis factor (TNF)-a-and Fas-mediated apoptosis than those from the wild-type. 8) Moreover, histological and biochemical analyses of livers from SMP30 knockout mice showed abnormal accumulations of neutral lipids and phospholipids.9) This abnormal lipid metabolism must increase the tissues' susceptibility to apoptosis. Such changes of SMP30 expression might, then, account for the deterioration of cellular functions and lowered resistance to harmful stimuli in aged tissues.We recently identified SMP30 as a gluconolactonase (GNL, EC 3.1.1.17) that is involved in the vitamin C biosynthetic pathway and found that SMP30/GNL knockout mice cannot synthesize vitamin C in vivo.10) Humans, monkeys and guinea pigs are similarly incapable of synthesizing vitamin C in vivo, because the gluconolactone oxidase gene has mutated throughout evolution; however, mice, rats and many other animals do synthesize vitamin C in vivo. With aging, SMP30/GNL content decreases in the liver, kidney and lung, and such decreases affect the normally copious amount of SMP30/GNL in the livers of younger humans.2) To discern what, if any, functions SMP30/GNL has in the human liver, we transfected the Hep G2 human liver carcinoma cell line with the human SMP30/GNL gene. In the present study, we found that the over-expression of SMP30/GNL in these Hep G2 cells contributed to the decrease of reactive oxygen species (ROS) formation, presumably increasing the cells' state of oxidative stress. MATERIALS AND METHODSCell Culture Stable transfectants expressing the human SMP30/GNL were established as described p...

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Regucalcin confers resistance to amyloid‐β toxicity in neuronally differentiated PC12 cells

et al. 2018

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Amyloid‐β (Aβ), a primary component of amyloid plaques, has been widely associated with the pathogenesis of Alzheimer's disease. The Ca 2+ ‐binding protein regucalcin (RGN) plays multiple roles in maintaining cell functions by regulating intracellular calcium homeostasis, various signaling pathways, and gene expression systems. Here, we investigated the functional role of RGN against Aβ‐induced cytotoxicity in neuronally differentiated PC 12 cells. Overexpression of RGN reduced Aβ‐induced apoptosis by reducing mitochondrial dysfunction and caspase activation. It also attenuated Aβ‐induced reactive oxygen species production and oxidative damage and decreased Aβ‐induced nitric oxide (NO) overproduction, upregulation of inducible NO synthase by nuclear factor‐κB, and nitrosative damage. Interestingly, the genetic disruption of RGN increased the susceptibility of neuronally differentiated PC 12 cells to Aβ toxicity. Thus, RGN possesses antioxidant activity against Aβ‐induced oxidative and nitrosative stress and may play protective roles against Aβ‐induced neurotoxicity in Alzheimer's disease.

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SMP30 deficiency in mice causes an accumulation of neutral lipids and phospholipids in the liver and shortens the life span

Cited by 100 publications

References 25 publications

Senescence marker protein 30 functions as gluconolactonase in l -ascorbic acid biosynthesis, and its knockout mice are prone to scurvy

Senescence marker protein 30 functions as gluconolactonase in l -ascorbic acid biosynthesis, and its knockout mice are prone to scurvy

Over-expression of Senescence Marker Protein-30 Decreases Reactive Oxygen Species in Human Hepatic Carcinoma Hep G2 Cells

Regucalcin confers resistance to amyloid‐β toxicity in neuronally differentiated PC12 cells

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