Glucose-stimulated insulin secretion suppresses hepatic triglyceride-rich lipoprotein and apoB production

The current study assessed in vivo the effect of insulin on triglyceride-rich lipoprotein (TRL) production by rat liver. Hepatic triglyceride and apolipoprotein B (apoB) production were measured in anesthetized, fasted rats injected intravenously with Triton WR-1339 (400 mg/kg). After intravascular catabolism was blocked by detergent treatment, glucose (500 mg/kg) was injected to elicit insulin secretion, and serum triglyceride and apoB accumulation were monitored over the next 3 h. In glucose-injected rats, triglyceride secretion averaged 22.5 ± 2.1 μg · ml−1· min−1, which was significantly less by 30% than that observed in saline-injected rats, which averaged 32.1 ± 1.4 μg · ml−1· min−1. ApoB secretion was also significantly reduced by 66% in glucose-injected rats. ApoB immunoblotting indicated that both B100 and B48 production were significantly reduced after glucose injection. Results support the conclusion that insulin acts in vivo to suppress hepatic very low density lipoprotein (VLDL) triglyceride and apoB secretion and strengthen the concept of a regulatory role for insulin in VLDL metabolism postprandially.

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Causes of the triglyceride-lowering effect of exercise training in rats

Journal of Applied Physiology ◽

10.1152/jappl.1984.57.5.1466 ◽

1984 ◽

Vol 57 (5) ◽

pp. 1466-1471 ◽

Cited By ~ 31

Author(s):

C. E. Mondon ◽

C. B. Dolkas ◽

T. Tobey ◽

G. M. Reaven

Keyword(s):

Exercise Training ◽

Serum Insulin ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Serum Triglyceride ◽

Perfused Liver ◽

And Control ◽

The Relationship ◽

Intact Rats

Serum triglyceride (TG) levels are lower in exercise-trained (ET) compared with control rats throughout a 24-h period (P less than 0.01–0.001). To understand this phenomenon, the relationship between serum TG concentration and hepatic very low density lipoprotein (VLDL)-TG secretion rate was studied in intact rats. In addition, hepatic TG secretion was measured in isolated perfused liver and TG removal by isolated perfused hindlimbs at rest and during simulated exercise. In vivo, low TG levels are consistently associated with decreased serum insulin concentration and periodic decrease in free fatty acid (FFA) levels. At rest, with comparable FFA levels, VLDL-TG secretion was 50% lower in ET rats, proportionate to the reduction in serum TG levels. Hepatic TG secretion by perfused livers of ET and control rats was similar when studied at comparable FFA and insulin levels suggesting the fall in VLDL-TG secretion with exercise training was not the result of intrinsic change in the ability of the liver to esterify and secrete TG. Perfused muscle of ET and control rats remove TG at equal rates when perfused at rest. However, during simulated exercise, TG removal was increased only in hindlimbs from ET rats. Thus, low serum TG levels in ET rats seem to be due to a combined effect of decreased hepatic TG secretion, secondary to reduced substrate and insulin supply to the liver, and increased TG removal by muscle during exercise.

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Kinesin-dependent mechanism for controlling triglyceride secretion from the liver

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1713292114 ◽

2017 ◽

Vol 114 (49) ◽

pp. 12958-12963 ◽

Cited By ~ 20

Author(s):

Priyanka Rai ◽

Mukesh Kumar ◽

Geetika Sharma ◽

Pradeep Barak ◽

Saumitra Das ◽

...

Keyword(s):

Energy Homeostasis ◽

Smooth Endoplasmic Reticulum ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Serum Triglyceride ◽

Homeostatic Control ◽

Fed State ◽

Triglyceride Secretion ◽

Triglyceride Content ◽

Lipoprotein Assembly

Despite massive fluctuations in its internal triglyceride content, the liver secretes triglyceride under tight homeostatic control. This buffering function is most visible after fasting, when liver triglyceride increases manyfold but circulating serum triglyceride barely fluctuates. How the liver controls triglyceride secretion is unknown, but is fundamentally important for lipid and energy homeostasis in animals. Here we find an unexpected cellular and molecular mechanism behind such control. We show that kinesin motors are recruited to triglyceride-rich lipid droplets (LDs) in the liver by the GTPase ARF1, which is a key activator of lipolysis. This recruitment is activated by an insulin-dependent pathway and therefore responds to fed/fasted states of the animal. In fed state, ARF1 and kinesin appear on LDs, consequently transporting LDs to the periphery of hepatocytes where the smooth endoplasmic reticulum (sER) is present. Because the lipases that catabolize LDs in hepatocytes reside on the sER, LDs can now be catabolized efficiently to provide triglyceride for lipoprotein assembly and secretion from the sER. Upon fasting, insulin is lowered to remove ARF1 and kinesin from LDs, thus down-regulating LD transport and sER–LD contacts. This tempers triglyceride availabiity for very low density lipoprotein assembly and allows homeostatic control of serum triglyceride in a fasted state. We further show that kinesin knockdown inhibits hepatitis-C virus replication in hepatocytes, likely because translated viral proteins are unable to transfer from the ER to LDs.

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Selective deficiency of hepatic triglyceride lipase and hypertriglyceridaemia in kwashiorkor

British Journal Of Nutrition ◽

10.1079/bjn19790124 ◽

1979 ◽

Vol 42 (3) ◽

pp. 351-356 ◽

Cited By ~ 8

Author(s):

E. O. Agbedana ◽

A. O. Johnson ◽

G. Oladunni Taylor

Keyword(s):

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Serum Triglyceride ◽

Hepatic Triglyceride ◽

Normal Range ◽

Control Value ◽

Malnourished Children ◽

Before And After ◽

The Mean ◽

Definite Correlation

1. Serum postheparin lipolytic activities (PHLA), triglyceride and free fatty acid concentrations were determined in children with kwashiorkor before and after treatment and also in normal control children.2. Using the range (571–1650 μmol/l) of serum triglyceride of the control children as normal, five (20%) of the twenty-five children with kwashiorkor had low (less than 570μmol/l), thirteen (52%) had normal (571–1650, μmol/l) and seven (28%) had high (more than 1650 μmol/l) serum triglyceride levels.3. The serum PHLA did not show any definite correlation with the level of circulating triglycerides, although the lowest levels of PHLA were found in the malnourished children with highest triglyceride level.4. While the hepatic PHLA in the malnourished children was significantly less than control value, the extrahepatic PHLA did not differ significantly.5. After treatment, serum PHLA rose significantly and the mean levels were within normal range.6. Our findings suggest that a defect in catabolism of very-low-density lipoprotein caused by a low hepatic PHLA may cause hypertriglyceridaemia in children with kwashiorkor.

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Lpcat3-dependent production of arachidonoyl phospholipids is a key determinant of triglyceride secretion

eLife ◽

10.7554/elife.06557 ◽

2015 ◽

Vol 4 ◽

Cited By ~ 67

Author(s):

Xin Rong ◽

Bo Wang ◽

Merlow M Dunham ◽

Per Niklas Hedde ◽

Jinny S Wong ◽

...

Keyword(s):

Metabolic Pathways ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Membrane Lipid ◽

Membrane Composition ◽

Critical Determinant ◽

Triglyceride Secretion ◽

Key Factor

The role of specific phospholipids (PLs) in lipid transport has been difficult to assess due to an inability to selectively manipulate membrane composition in vivo. Here we show that the phospholipid remodeling enzyme lysophosphatidylcholine acyltransferase 3 (Lpcat3) is a critical determinant of triglyceride (TG) secretion due to its unique ability to catalyze the incorporation of arachidonate into membranes. Mice lacking Lpcat3 in the intestine fail to thrive during weaning and exhibit enterocyte lipid accumulation and reduced plasma TGs. Mice lacking Lpcat3 in the liver show reduced plasma TGs, hepatosteatosis, and secrete lipid-poor very low-density lipoprotein (VLDL) lacking arachidonoyl PLs. Mechanistic studies indicate that Lpcat3 activity impacts membrane lipid mobility in living cells, suggesting a biophysical basis for the requirement of arachidonoyl PLs in lipidating lipoprotein particles. These data identify Lpcat3 as a key factor in lipoprotein production and illustrate how manipulation of membrane composition can be used as a regulatory mechanism to control metabolic pathways.

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Impaired-Inactivation of FoxO1 Contributes to Glucose-Mediated Increases in Serum Very Low-Density Lipoprotein

Endocrinology ◽

10.1210/en.2010-0204 ◽

2010 ◽

Vol 151 (8) ◽

pp. 3566-3576 ◽

Cited By ~ 13

Author(s):

Ke Wu ◽

David Cappel ◽

Melissa Martinez ◽

John M. Stafford

Keyword(s):

Blood Glucose ◽

De Novo ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Serum Triglyceride ◽

Very Low Density Lipoprotein ◽

Low Density ◽

Experimental Conditions ◽

Adenoviral Delivery

For patients with diabetes, insulin resistance and hyperglycemia both contribute to increased serum triglyceride in the form of very low-density lipoprotein (VLDL). Our objective was to define the insulin conditions in which hyperglycemia promotes increased serum VLDL in vivo. We performed hyperglycemic-hyperinsulinemic clamp studies and hyperglycemic-hypoinsulinemic clamp studies in rats, with metabolic tracers for glucose flux and de novo fatty acid synthesis. When blood glucose was clamped at hyperglycemia (17 mm) for 2 h under hyperinsulinemic conditions (4 mU/kg · min), serum VLDL levels were not increased compared with baseline. We speculated that hyperinsulinemia minimized glucose-mediated VLDL changes and performed hyperglycemic-hypoinsulinemic clamp studies in which insulin was clamped near fasting levels with somatostatin (17 mm blood glucose, 0.25 mU/kg · min insulin). Under low-insulin conditions, serum VLDL levels were increased 4.7-fold after hyperglycemia, and forkhead box O1 (FoxO1) was not excluded from the nucleus of liver cells. We tested the extent that impaired inactivation of FoxO1 by insulin was sufficient for glucose to promote increased serum VLDL. We found that, when the ability of insulin to inactivate FoxO1 is blocked after adenoviral delivery of constitutively active FoxO1, glucose increased serum VLDL triglyceride when given both by ip glucose tolerance testing (3.5-fold increase) and by a hyperglycemic clamp (4.6-fold). Under both experimental conditions in which insulin signaling to FoxO1 was impaired, we found increased activation of carbohydrate response element binding protein. These data suggest that glucose more potently promotes increased serum VLDL when insulin action is impaired, with either low insulin levels or disrupted downstream signaling to the transcription factor FoxO1.

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2072-P: Deletion of the Mitofusins 1 and 2 (Mfn1 and Mfn2) in the Pancreatic Beta Cell Disrupts Mitochondrial Structure and Function In Vitro and Strongly Impairs Glucose-Stimulated Insulin Secretion In Vivo

Diabetes ◽

10.2337/db20-2072-p ◽

2020 ◽

Vol 69 (Supplement 1) ◽

pp. 2072-P

Author(s):

ELENI GEORGIADOU ◽

PAULINE L. CHABOSSEAU ◽

ALEJANDRA TOMAS ◽

ISABELLE LECLERC ◽

GUY A. RUTTER

Keyword(s):

Insulin Secretion ◽

Beta Cell ◽

Pancreatic Beta Cell ◽

Structure And Function ◽

Insulin Secretion In Vivo ◽

Mitochondrial Structure ◽

Glucose Stimulated Insulin Secretion ◽

And Function

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Oxidation of Plasma Low-Density Lipoprotein Accelerates Its Accumulation and Degradation in the Arterial Wall In Vivo

Circulation ◽

10.1161/01.cir.94.7.1698 ◽

1996 ◽

Vol 94 (7) ◽

pp. 1698-1704 ◽

Cited By ~ 46

Author(s):

Klaus Juul ◽

Lars B. Nielsen ◽

Klaus Munkholm ◽

Steen Stender ◽

Børge G. Nordestgaard

Keyword(s):

Arterial Wall ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Low Density

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Interaction of 4-hydroxynonenal-modified low-density lipoproteins with the fibroblast apolipoprotein B/E receptor

Biochemical Journal ◽

10.1042/bj2340245 ◽

1986 ◽

Vol 234 (1) ◽

pp. 245-248 ◽

Cited By ~ 31

Author(s):

W Jessup ◽

G Jurgens ◽

J Lang ◽

H Esterbauer ◽

R T Dean

Keyword(s):

Apolipoprotein B ◽

Negative Charge ◽

Low Density Lipoprotein ◽

Ldl Receptor ◽

Density Lipoprotein ◽

Low Density ◽

Lipid Peroxidation Product ◽

Modified Low Density Lipoproteins ◽

Peroxidation Product

The incorporation of the lipid peroxidation product 4-hydroxynonenal into low-density lipoprotein (LDL) increases the negative charge of the particle, and decreases its affinity for the fibroblast LDL receptor. It is suggested that this modification may occur in vivo, and might promote atherogenesis.

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