The glucagon-like peptide 1 receptor is essential for postprandial lipoprotein synthesis and secretion in hamsters and mice

Hsieh, Joanne; Longuet, Christine; Baker, Christopher L.; Qin, Bolin; Federico, Lisa; Drucker, Daniel J.; Adeli, Khosrow

doi:10.1007/s00125-009-1611-5

Cited by 232 publications

(234 citation statements)

References 34 publications

(35 reference statements)

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“…The mechanism of improvement in hepatic lipoprotein production in this study remains to be further elucidated, although it is likely explained by indirect factors, such as improvement in glycemia with chronic use, rather than direct inhibition of hepatic lipoprotein synthesis and secretion. In contrast, a direct action of GLP-1 on intestinal lipoprotein production is supported by ex vivo studies in isolated hamster intestinal enterocytes, where exendin-4 inhibited apoB-48 secretion into the medium (56). Consistent with this, GLP-1R expression has been identified in the small intestine of humans (59).…”

Section: Mechanisms Whereby Glp-1r Agonists and Dpp-4 Inhibitors Amelmentioning

confidence: 71%

“…In healthy individuals receiving intraduodenal lipid infusion, GLP-2 increased TRL apoB-48 more robustly than TRL TG under pancreatic clamp conditions (76), suggesting release of smaller, less lipidated particles. Acute GLP-2 treatment of healthy hamsters raised both postprandial TG and apoB-48 concentrations, in part via enhanced CD36-mediated fatty acid uptake (56). An increase in TG accumulation in the chylomicron fractions of the plasma was observed with GLP-2 treatment, as assessed by fast-protein liquid chromatography (S. Farr, K. Adeli, unpublished data); however, further studies are needed to assess whether this can be attributed to increased particle number, size, or both.…”

Section: Glp-2 Stimulates "Preformed" Intestinal Lipoprotein Particlementioning

confidence: 96%

“…This indicates that the GLP-1 effect on intestinal lipid handling may occur between the intestinal lumen and lymph output. In hamsters, administration of sitagliptin or exendin-4 (a GLP-1R agonist) prior to oral fat load decreased TRL TG and apoB-48 accumulation in the circulation following triton injection (56). However, when exendin-4 was given 1 h after oral gavage of olive oil to allow lipids to pass through the stomach into the duodenum (i.e., to circumvent the slowing of gastric emptying by GLP-1), the suppression in TG and apoB-48 was not abolished (56).…”

Section: Mechanisms Whereby Glp-1r Agonists and Dpp-4 Inhibitors Amelmentioning

confidence: 99%

“…In hamsters, administration of sitagliptin or exendin-4 (a GLP-1R agonist) prior to oral fat load decreased TRL TG and apoB-48 accumulation in the circulation following triton injection (56). However, when exendin-4 was given 1 h after oral gavage of olive oil to allow lipids to pass through the stomach into the duodenum (i.e., to circumvent the slowing of gastric emptying by GLP-1), the suppression in TG and apoB-48 was not abolished (56). Our recent studies in healthy humans support an acute, direct inhibitory effect of incretin-based therapies on intestinal lipoprotein production (49,50).…”

Section: Mechanisms Whereby Glp-1r Agonists and Dpp-4 Inhibitors Amelmentioning

confidence: 99%

“…GLP-1R agonists have been shown to lower postprandial TG concentration in healthy and insulinresistant humans following ingestion of a high-fat meal (36,37), as well as in rats, hamsters, and mice following oral lipid administration (56,62). A reduction in TRL TG concentration could be explained by fewer particles of unchanged size, smaller particles (carrying less TG per particle) but unchanged number, or the combination in which there are fewer particles that are also reduced in size.…”

Section: Mechanisms Whereby Glp-1r Agonists and Dpp-4 Inhibitors Amelmentioning

confidence: 99%

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Gut Peptides Are Novel Regulators of Intestinal Lipoprotein Secretion: Experimental and Pharmacological Manipulation of Lipoprotein Metabolism

et al. 2015

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Individuals with metabolic syndrome and frank type 2 diabetes are at increased risk of atherosclerotic cardiovascular disease, partially due to the presence of lipid and lipoprotein abnormalities. In these conditions, the liver and intestine overproduce lipoprotein particles, exacerbating the hyperlipidemia of fasting and postprandial states. Incretin-based, antidiabetes therapies (i.e., glucagon-like peptide [GLP]-1 receptor agonists and dipeptidyl peptidase-4 inhibitors) have proven efficacy for the treatment of hyperglycemia. Evidence is accumulating that these agents also improve fasting and postprandial lipemia, the latter more significantly than the former. In contrast, the gut-derived peptide GLP-2, cosecreted from intestinal L cells with GLP-1, has recently been demonstrated to enhance intestinal lipoprotein release. Understanding the roles of these emerging regulators of intestinal lipoprotein secretion may offer new insights into the regulation of intestinal lipoprotein assembly and secretion and provide new opportunities for devising novel strategies to attenuate hyperlipidemia, with the potential for cardiovascular disease reduction.

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Section: Mechanisms Whereby Glp-1r Agonists and Dpp-4 Inhibitors Amelmentioning

confidence: 71%

Section: Glp-2 Stimulates "Preformed" Intestinal Lipoprotein Particlementioning

confidence: 96%

Section: Mechanisms Whereby Glp-1r Agonists and Dpp-4 Inhibitors Amelmentioning

confidence: 99%

Section: Mechanisms Whereby Glp-1r Agonists and Dpp-4 Inhibitors Amelmentioning

confidence: 99%

Section: Mechanisms Whereby Glp-1r Agonists and Dpp-4 Inhibitors Amelmentioning

confidence: 99%

See 3 more Smart Citations

Gut Peptides Are Novel Regulators of Intestinal Lipoprotein Secretion: Experimental and Pharmacological Manipulation of Lipoprotein Metabolism

et al. 2015

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Current literature in diabetes

2010

Diabetes Metabolism Res

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In order to keep subscribers up‐to‐date with the latest developments in their field, John Wiley & Sons are providing a current awareness service in each issue of the journal. The bibliography contains newly published material in the field of diabetes/metabolism. Each bibliography is divided into 26 sections: 1 Reviews; 2 General; 3 Genetics; 4 Epidemiology; 5 Immunology; 6 Obesity; 7 Prediction and Prevention; 8 Intervention: a) General; b) Care; c) Drug Therapy; d)Economics; e) Gene therapy; f) Nursing; g) Nutrition; h) Surgery; i) Transplantation; 9 Pathology and Complications: a) General; b) Cardiovascular; c) Eye disease; d) Gestational and fetal; e) Neurological; f) Podiatrical; g) Renal; 10 Endocrinology & Metabolism; 11 Experimental Studies; 12 Diagnosis and Techniques. Within each section, articles are listed in alphabetical order with respect to author

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Hepatic Fibroblast Growth Factor 21 Is Involved in Mediating Functions of Liraglutide in Mice With Dietary Challenge

et al. 2021

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Background and Aims Several studies have shown that expression of hepatic fibroblast growth factor 21 (FGF21) can be stimulated by glucagon‐like peptide 1 (GLP‐1)–based diabetes drugs. As GLP‐1 receptor (GLP‐1R) is unlikely to be expressed in hepatocytes, we aimed to compare such stimulation in mice and in mouse hepatocytes, determine the involvement of GLP‐1R, and clarify whether FGF21 mediates certain functions of the GLP‐1R agonist liraglutide. Approach and Results Liver FGF21 expression was assessed in mice receiving a daily liraglutide injection for 3 days or in mouse primary hepatocytes (MPHs) undergoing direct liraglutide treatment. The effects of liraglutide on metabolic improvement and FGF21 expression were then assessed in high‐fat diet (HFD)‐fed mice and compared with the effects of the dipeptidyl‐peptidase 4 inhibitor sitagliptin. Animal studies were also performed in Glp1r−/− mice and liver‐specific FGF21‐knockout (lFgf21‐KO) mice. In wild‐type mouse liver that underwent RNA sequencing and quantitative reverse‐transcription PCR, we observed liraglutide‐stimulated hepatic Fgf21 expression and a lack of Glp1r expression. In MPHs, liraglutide did not stimulate Fgf21. In mice with HFD‐induced obesity, liraglutide or sitagliptin treatment reduced plasma triglyceride levels, whereas their effect on reducing body‐weight gain was different. Importantly, increased hepatic FGF21 expression was observed in liraglutide‐treated mice but was not observed in sitagliptin‐treated mice. In HFD‐fed Glp1r−/− mice, liraglutide showed no beneficial effects and could not stimulate Fgf21 expression. In lFgf21‐KO mice undergoing dietary challenge, the body‐weight‐gain attenuation and lipid homeostatic effects of liraglutide were lost or significantly reduced. Conclusions We suggest that liraglutide‐stimulated hepatic Fgf21 expression may require GLP‐1R to be expressed in extrahepatic organs. Importantly, we revealed that hepatic FGF21 is required for liraglutide to lower body weight and improve hepatic lipid homeostasis. These observations advanced our mechanistic understanding of the function of GLP‐1–based drugs in NAFLD.

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The glucagon-like peptide 1 receptor is essential for postprandial lipoprotein synthesis and secretion in hamsters and mice

Cited by 232 publications

References 34 publications

Gut Peptides Are Novel Regulators of Intestinal Lipoprotein Secretion: Experimental and Pharmacological Manipulation of Lipoprotein Metabolism

Gut Peptides Are Novel Regulators of Intestinal Lipoprotein Secretion: Experimental and Pharmacological Manipulation of Lipoprotein Metabolism

Current literature in diabetes

Hepatic Fibroblast Growth Factor 21 Is Involved in Mediating Functions of Liraglutide in Mice With Dietary Challenge

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