Enhanced expression of hepatic acyl-coenzyme A synthetase and microsomal triglyceride transfer protein messenger RNAs in the obese and hypertriglyceridemic rat with visceral fat accumulation

Kuriyama, Hiroshi; Yamashita, Shizuya; Shimomura, Iichiro; Funahashi, Tohru; Ishigami, Masato; Aragane, Katsumi; Miyaoka, Kouji; Nakamura, Tadashi; Takemura, Koichi; Man, Zhiwei; Toide, Kiyotaka; Nakayama, Natsuki; Fukuda, Yoshimasa; Lin, Marie C.; Wetterau, John R.; Matsuzawa, Yūji

doi:10.1002/hep.510270233

Cited by 81 publications

(45 citation statements)

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“…Such differences in the analytical approaches used may explain discrepancies between their results and ours. In viscerally obese rats (OLETF rats) at 6 weeks, before the development of insulin resistance, a significant increase of MTP mRNA *P P value adjusted for age **P P value adjusted for age and visceral adipose tissue (AT) levels was observed whereas apoB mRNA levels were similar to those observed in normal rats (LETO rats) (Kuriyama et al 1998). In viscerally obese men, the À493G>T polymorphism has been associated with CETP gene expression, but the precise mechanism whereby CETP regulates apoB is unclear.…”

Section: Discussionmentioning

confidence: 85%

Molecular screening of the microsomal triglyceride transfer protein: association between polymorphisms and both abdominal obesity and plasma apolipoprotein B concentration

et al. 2004

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Microsomal triglyceride transfer protein (MTP) plays a critical role in the assembly of lipoproteins. The aim of this study was first to seek new MTP gene variants and then to verify whether MTP gene polymorphisms were associated with plasma lipoprotein/lipid levels in men with visceral obesity. Molecular screening of the MTP gene revealed 11 polymorphisms. The carriers of the c.933A allele and c.1151C allele or À400A/A homozygotes were characterized by increased levels of abdominal visceral adipose tissue (AT) measured by computed tomography (P=0.02, P=0.04, P=0.03, respectively). After dividing each genotype group into subgroups using 130 cm 2 as a cutoff point for visceral AT, significantly higher low-density lipoprotein (LDL)-apolipoprotein B (apoB) concentrations were found in obese men bearing the c.891G allele, the À400 T allele, as well as for 282G/G homozygotes, 933C/C homozygotes, and 1151A/A homozygotes when compared to their lean counterparts. Haplotypes were not associated with phenotypes under study. In conclusion, some MTP gene polymorphisms in the French Canadian population are associated with the amount of abdominal visceral AT and plasma LDL-apoB concentrations.

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Section: Discussionmentioning

confidence: 85%

Molecular screening of the microsomal triglyceride transfer protein: association between polymorphisms and both abdominal obesity and plasma apolipoprotein B concentration

et al. 2004

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“…A lipid enrichment of the diet stimulates the hepatic expression of MTP mRNA in hamsters in a dose-dependent manner (37), and the genetically obese OLEFT rat, which has increased fatty acid levels in the portal vein, also displays increased hepatic MTP activity and lipoprotein secretion (38). This has led to the suggestion that prolonged increases in flux of fatty acid to the liver may stimulate MTP expression (38). The present data are in accordance with this idea because an elevation of MTP expression in ob/ob mice occurred in the setting of increased triglyceride clearance from the blood as well as increased triglyceride stores in the liver.…”

Section: Discussionmentioning

confidence: 99%

Hepatic Expression of Microsomal Triglyceride Transfer Protein and In Vivo Secretion of Triglyceride-Rich Lipoproteins Are Increased in Obese Diabetic Mice

2002

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Secondary hyperlipidemia is a major cardiovascular risk factor in individuals with type 2 diabetes. Increased hepatic production of apolipoprotein B (apoB)-containing lipoproteins contributes to the elevated plasma levels, but the mechanism is poorly understood. Recent results have established that microsomal triglyceride transfer protein (MTP) is rate limiting for the assembly and secretion of apoB-containing lipoproteins. To better understand the mechanism of type 2 diabetes-associated hyperlipidemia, we quantified hepatic MTP mRNA levels, hepatic microsomal triglyceride transfer activity, and in vivo triglyceride secretion from the liver in two diabetic mouse models. Obese diabetic (ob/ob) mice had 45% higher (P ‫؍‬ 0.006) hepatic MTP mRNA levels, 54% higher (P < 0.0001) microsomal triglyceride transfer activity, and 70% higher (P < 0.0001) in vivo triglyceride secretion rates compared with ob/؉ control mice. In contrast, in lean streptozotocin-treated diabetic mice, hepatic MTP mRNA levels were unchanged, whereas microsomal triglyceride transfer activity and in vivo triglyceride secretion rates were marginally decreased. These studies suggest that obesity-induced type 2 diabetes in mice confers increases in hepatic MTP expression and secretion of triglyceride-rich lipoproteins. High blood glucose and altered hepatic expression of sterol regulatory element binding protein genes play a minor role in this diabetic response. Diabetes 51: 1233-1239, 2002 T he incidence and prevalence of type 2 diabetes are rapidly rising (1). Individuals with type 2 diabetes have an increased risk of cardiovascular disease, which is closely associated with elevation of the plasma levels of apolipoprotein B (apoB)-containing VLDL and LDL (2,3). Metabolic labeling studies have indicated that the increased plasma levels of VLDL and LDL in individuals with diabetes are caused, at least in part, by increased hepatic secretion of apoB-containing lipoproteins (4,5). Hence, a better understanding of the factors in patients with type 2 diabetes that mediate increased lipoprotein secretion from the liver could potentially lead to rational therapeutic strategies to prevent cardiovascular disease in this patient group.During the past 5 years, it has become evident that microsomal triglyceride transfer protein (MTP) is rate limiting for the production of apoB-containing VLDL (6 -10). MTP is an exclusively intracellular protein (6). Its principal role is to transfer lipids onto the apoB polypeptide in the endoplasmic reticulum of lipoprotein-secreting cells (6). Reduction of the MTP activity in animals by MTP inhibitor drugs (7) or genetic manipulations (11,12) lowers plasma lipoprotein levels, whereas adenoviral overexpression of an MTP cDNA in mouse liver in vivo increases hepatic secretion of triglyceride-rich apoB-containing lipoproteins (13,14).Studies of cultured liver cells suggest that insulin and glucose reduce the expression of the MTP gene (15); the MTP gene promoter region contains a putative insulinresponsive element (16). Also, r...

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“…Our group reported that FFA enhance mRNA expression of microsomal triglyceride transfer protein in the liver, which suggests that increased FFA influx to the liver from visceral fat may contribute increased very-low-density lipoprotein formation and secretion, and results in hyperlipidemia. 18 In contrast to the observation on FFA metabolism, the fate of glycerol, another metabolite of triglyceride lipolysis, has not been well investigated. …”

Section: Fat Topography Y Matsuzawamentioning

confidence: 99%

The role of fat topology in the risk of disease

Matsuzawa

2008

Int J Obes

106

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Clustering of multiple risk factors such as impaired glucose metabolism, lipid disorders and hypertension has been shown to be the major background of atherosclerotic diseases, and disease entities such as the metabolic syndrome represent a highly atherogenic state. Although these common risks may generally co-exist by accident in one individual, clustering of multiple risk factors in the metabolic syndrome does not occur by accident, and there should be a key player for the syndrome. In 1983, we reported the method for fat analysis using computed tomography scan, which enables us to analyze intra-abdominal visceral adiposity as well as subcutaneous fat. Visceral fat accumulation has been shown to cause impaired glucose metabolism, lipid disorders, and hypertension, and therefore it is considered to be a key player in the metabolic syndrome. To clarify the mechanism by which visceral fat accumulation causes a variety of metabolic and vascular diseases, we studied the molecular characteristics of adipose tissue and adipocytes by investigating expressed genes in visceral and subcutaneous adipocytes and revealed that adipocytes, especially visceral adipocytes, secrete a variety of bioactive substances, the so-called adipocytokines. We showed that visceral fat accumulation causes abnormalities in adipocytokine secretion, such as hypersecretion of plasminogen activator inhibitor 1, which is related to thrombogenic vascular diseases. More importantly, we discovered an important benign adipocytokine named adiponectin, which protects against the development of diabetes mellitus, hypertension, inflammation, and atherosclerotic vascular diseases. Plasma levels of adiponectin decreased in individuals with visceral fat accumulation, and hypoadiponectinemia caused by visceral fat accumulation might be one of the major causes of metabolic syndrome.

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Enhanced expression of hepatic acyl-coenzyme A synthetase and microsomal triglyceride transfer protein messenger RNAs in the obese and hypertriglyceridemic rat with visceral fat accumulation

Cited by 81 publications

References 50 publications

Molecular screening of the microsomal triglyceride transfer protein: association between polymorphisms and both abdominal obesity and plasma apolipoprotein B concentration

Molecular screening of the microsomal triglyceride transfer protein: association between polymorphisms and both abdominal obesity and plasma apolipoprotein B concentration

Hepatic Expression of Microsomal Triglyceride Transfer Protein and In Vivo Secretion of Triglyceride-Rich Lipoproteins Are Increased in Obese Diabetic Mice

The role of fat topology in the risk of disease

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