Involvement of senescence marker protein‐30 in glucose metabolism disorder and non‐alcoholic fatty liver disease

Abstract

Senescence marker protein-30 (SMP30) was found to decrease in the liver, kidneys and lungs of mice during aging. SMP30 is a pleiotropic protein that acts to protect cells from apoptosis by enhancing plasma membrane Ca 2+ -pump activity and is bona fide gluconolactonase (EC 3.1.1.17) that participates in the penultimate step of the vitamin C biosynthetic pathway. For the past several years, we have obtained strong evidence showing the close relationship between SMP30, glucose metabolism disorder and non-alchoholic fatty liver disease in experiments with SMP30 knockout mice. Emerging proof links the following abnormalities: (i) the reduction of SMP30 by aging and/or excessive dietary fat or genetic deficiency causes a loss of Ca 2+ pumping activity, which impairs acute insulin release in pancreatic β-cells, initiates inflammatory responses with oxidative stress and endoplasmic reticulum stress in non-alchoholic steatohepatitis, exacerbates renal tubule damage, and introduces tubulointerstitial inflammation and fibrosis in diabetic nephropathy; (ii) vitamin C insufficiency also impairs acute insulin secretion in pancreatic β-cells by a mechanism distinct from that of the SMP30 deficiency; and (iii) the increased oxidative stress by concomitant deficiencies of SMP30, superoxide dismutase 1 and vitamin C similarly causes hepatic steatosis. Here, we review recent advances in our understanding of SMP30 in glucose metabolism disorder and non-alchoholic fatty liver disease. Geriatr Gerontol Int 2016; 16 (Suppl. 1): 4-16.Keywords: aging, diabetes mellitus, non-alchoholic fatty liver disease, senescence marker protein-30, vitamin C. Senescence marker protein-30 and its knockout miceSenescence marker protein-30 (SMP30) was first discovered in 1991 as an age-associated protein that decreased quantifiably in livers of aged rats.1,2 Thereafter, SMP30 proved to decrease in the liver, kidneys and lungs of mice during aging.3-5 Immunohistochemical analysis in the liver and primary cultured hepatocytes showed that SMP30 staining appeared in some, but not all, parenchymal cells, and localized in both the nuclei and cytoplasm.5 Furthermore, SMP30-positive cells localized mainly around the central veins in the livers of mice, and decreased numerically with aging.5 As established by reverse transcription polymerase chain reaction analysis, SMP30 transcripts were detected in not only the liver, kidneys and lungs of mice, but also in their brain, thymus, heart, testes and ovary; however, no SMP30 transcripts were identified in the spleen. 4,6 In humans, SMP30 was seen in parenchymal cells of the liver, proximal tubular cells of the kidney, acinal and ductal cells of the pancreas, and fasciculate cells of the adrenal cortex by applying immunohistochemical stain. 2,7 The human SMP30 gene is located in the p11.3-q11.2 segment of the X chromosome, 8 and its amino acid sequences are highly conserved among vertebrates. 7SMP30 knockout mice were established as a laboratory strain to clarify the physiological functions and the relationships bet...

Apoptosis and non-alcoholic fatty liver diseases

“…Circulating DPP4 activity correlates with measures of hepatocyte apoptosis and fibrosis in NAFLD in patients with type 2 diabetes mellitus and/or obesity[ 93 ]. Senescence marker protein-30 is involved in both glucose metabolism disorder and NAFLD[ 94 ].…”

Genomic deletion of GIT2 induces a premature age-related thymic dysfunction and systemic immune system disruption

“…Systemic and single cellular metabolic disruption, linked to either mitochondrial insufficiency or dysfunctional glucose uptake/transport, represents one of core features of aging as this pathophysiology can further entrain oxidative damage to lipids, nucleic acids and proteins. Given this, it is unsurprising that age-related diseases including Metabolic Syndrome/Type II diabetes mellitus (T2DM) [12], nonalcoholic steatohepatitis (NASH: [13]), cardiovascular disease [14], chronic kidney disease [15] and central neurodegenerative disorders such as Alzheimer's and Huntington's disease [16, 17] are strongly influenced by aberrant glucose metabolism.…”

Regucalcin enhances adipocyte differentiation and attenuates inflammation in 3T3‐L1 cells

“…In vitro studies using islets of RGN KO mice have shown that deficiency of RGN impairs insulin secretion to glucose or potassium chloride, suggesting the involvement of RGN in insulin secretion in pancreatic b-cells [7,9]. Studies on in vivo RGN KO mice also revealed that RGN is related to the pathogenesis of diabetic nephropathy, nonalcoholic fatty liver disease, and hepatic steatosis [10,11]. We also found support for a physiological role of RGN in maintaining the function of kidney proximal tubular epithelial cells [12].…”