Increased hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 in NIDDM

Cummings, Michael H.; Watts, Gerald F.; Umpleby, A. Margot; Hennessy, T. R.; Naoumova, R.P.; Slavin, B; Thompson, G. R.; S�nksen, P. H.

doi:10.1007/s001250050378

Cited by 48 publications

(57 citation statements)

References 37 publications

(63 reference statements)

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“…These previous observations all would support the prediction that type 2 diabetes is associated with decreased MTP gene expression in the liver. This seems to contrast with the findings of increased hepatic lipoprotein secretion in individuals with type 2 diabetes who are both hyperinsulinemic and hyperglycemic (21)(22)(23). These observations could also reflect that other factors, e.g., lipid availability in hepatocytes, are more important than MTP levels in determining lipoprotein secretion rates from the liver of individuals with diabetes or that MTP gene expression might be differently regulated in vivo than in cultured liver cells.…”

contrasting

confidence: 57%

“…These in vitro observations suggest that hepatic MTP gene expression might be decreased in individuals with hyperinsulinemic (type 2) diabetes. However, several metabolic studies have shown that individuals with type 2 diabetes display increased hepatic production of VLDL (21,24,34). The principal aim of the present study was to determine the effect of obesity-associated diabetes in mice on hepatic MTP gene expression, microsomal triglyceride transfer activity, and secretion of triglyceride-rich lipoproteins.…”

Section: Discussionmentioning

confidence: 93%

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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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contrasting

confidence: 57%

Section: Discussionmentioning

confidence: 93%

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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“…12,13 On the other hand, chronic hyperinsulinemia also has been associated with increased apoB-100 synthesis. 37 Differences in study conditions and methodologies make direct comparisons between remote studies difficult. Insulin levels were significantly greater in our NASH subjects than in either obese or lean controls.…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein synthesis in nonalcoholic steatohepatitis

et al. 2002

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The pathophysiology of hepatic steatosis, a prerequisite of nonalcoholic fatty liver disease, is poorly understood. Because very-low-density lipoprotein (VLDL) formation is the chief route of hepatic lipid export, we hypothesized that the synthesis of apoB-100, a rate-determining step in hepatic VLDL formation, may be altered in patients with nonalcoholic steatohepatitis (NASH). This study evaluated the relative synthesis rates of apolipoprotein B-100 (apoB-100) in patients with NASH and in lean and body mass index (BMI)-matched (obese) controls without NASH. A primed continuous infusion of L-[1-13 C] leucine was used to measure the absolute synthesis rates (ASR) of apoB-100 and fibrinogen in 7 patients with NASH and compared them with 7 lean and 7 obese (BMI-matched) controls without NASH. The ASRs of fibrinogen and albumin also were measured. The mean ASR of apoB-100 in patients with NASH was lower (31.5 ؎ 3.4 mg/kg/d) than that of obese (115.2 ؎ 7.2 mg/kg/d, P < .001) and lean controls (82.4 ؎ 4.1 mg/kg/d, P ‫؍‬ .002). In contrast, the mean ASR of fibrinogen was greater in subjects with NASH than in both control groups. These data indicate that NASH is associated with markedly altered hepatic synthesis of apoB-100. The finding that albumin synthesis was not similarly decreased in patients with NASH shows that the attenuation of apoB-100 synthesis is not on the basis of globally impaired hepatic protein synthesis. In conclusion, because apoB-100 synthesis is a rate-determining step in hepatocyte lipid export, decreased synthesis of this protein may be an important factor in the development of hepatic steatosis, a prerequisite for NASH. (HEPATOLOGY 2002;35:898-904.) N on-alcoholic steatohepatitis (NASH; part of the spectrum of nonalcoholic fatty liver disease) is characterized by macrovesicular steatosis, nuclear glycogenation, lobular and portal inflammation, and, occasionally, Mallory's hyaline, in the absence of excessive alcohol ingestion. 1 NASH is most frequently associated with obesity 2-9 and type 2 diabetes mellitus. 3,[7][8][9] Despite the high prevalence and the increasingly recognized morbidity associated with NASH, little is known about the pathophysiology of this condition. The liver is central to the regulation of fat metabolism, and the net accumulation of fat within hepatocytes, a prerequisite for steatosis and steatohepatitis, could potentially result from alterations in the uptake, synthesis, degradation, or secretory pathways of hepatic lipid metabolism.Apolipoprotein B-100 (apoB-100) is a large protein (512 kd) involved in the transport of triglycerides and cholesterol from the liver to peripheral tissues. Lipids are chiefly exported from the liver in the form of very-lowdensity lipoproteins (VLDL), a complex of protein (apoB-100), lipids (triglycerides or cholesteryl esters), and phospholipids. Although the mechanisms regulating the synthesis of apoB-100 are incompletely understood, the production of apoB-100 messenger RNA (mRNA) has been shown to be altered by insulin and unaffected by...

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“…Individuals with insulin resistance and diabetes are hyperinsulinemic and are resistant to the antilipolytic effect of insulin in peripheral tissues (15,16). Furthermore, hyperinsulinemic and insulin-resistant states are associated with VLDL oversecretion (17)(18)(19)(20)(21), which is the main cause of the elevation of TG-rich lipoproteins (TRLs) seen in these patients. The elevation in TRLs, in turn, contributes to their increased risk of cardiovascular disease (22,23).…”

mentioning

confidence: 99%

The Effect of Systemic Versus Portal Insulin Delivery in Pancreas Transplantation on Insulin Action and VLDL Metabolism

Carpentier¹,

Patterson

Uffelman³

et al. 2001

Diabetes

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Combined kidney-pancreas transplantation (KPT) with anastomosis of the pancreatic vein to the systemic circulation (KPT-S) or to the portal circulation (KPT-P) provides a human model in which the chronic effects of portal versus systemic insulin delivery on glucose and VLDL metabolism can be examined. Despite similar plasma glucose and C-peptide levels, KPT-S (n ‫؍‬ 9) had an approximate twofold elevation of fasting and intravenous glucose-stimulated plasma insulin levels compared with both KPT-P (n ‫؍‬ 7) and healthy control subjects (n ‫؍‬ 15). The plasma free fatty acid (FFA) levels were elevated in both transplant groups versus control subjects, but the plasma insulin elevation necessary to lower plasma FFA by 50% was approximately two times higher in KPT-S versus KPT-P and control subjects. Endogenous glucose production was similar in KPT-S and KPT-P, despite ϳ35% higher hepatic insulin levels in the latter, and was suppressed to a greater extent during a euglycemic-hyperinsulinemic clamp in KPT-S versus KPT-P. Total-body glucose utilization during the euglycemic-hyperinsulinemic clamp was ϳ40% lower in KPT-S versus KPT-P, indicating peripheral tissue but not hepatic insulin resistance in KPT-S versus KPT-P. Both transplant groups had an approximate twofold elevation of triglyceride (TG)-rich lipoprotein apolipoprotein B (apoB) and lipids versus control subjects. Elevation of VLDL-apoB and VLDL-TG in both transplant groups was entirely explained by an ϳ50% reduction in clearance of VLDL compared with healthy control subjects. In the presence of increased FFA load but in the absence of hepatic overinsulinization and marked hepatic insulin resistance, there was no elevation of VLDL secretion in KPT-S versus KPT-P and control subjects. These findings suggest that chronic systemic hyperinsulinemia and peripheral tissue insulin resistance with the consequent elevation of plasma FFA flux are insufficient per se to cause VLDL overproduction and that additional factors, such as hepatic hyperinsulinemia and/or gross insulin resistance, may be an essential prerequisite in the pathogenesis of VLDL overproduction in the common form of the insulin resistance syndrome.

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Increased hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 in NIDDM

Cited by 48 publications

References 37 publications

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

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

Apolipoprotein synthesis in nonalcoholic steatohepatitis

The Effect of Systemic Versus Portal Insulin Delivery in Pancreas Transplantation on Insulin Action and VLDL Metabolism

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