Diabetes Metab J.  2024 May;48(3):354-372. 10.4093/dmj.2023.0277.

Glucagon-Like Peptide-1: New Regulator in Lipid Metabolism

• Bu T
• Sun Z
• Pan Y
• Deng X
• Yuan G

• KMID: 2555767
• DOI: http://doi.org/10.4093/dmj.2023.0277

Abstract

Glucagon-like peptide-1 (GLP-1) is a 30-amino acid peptide hormone that is mainly expressed in the intestine and hypothalamus. In recent years, basic and clinical studies have shown that GLP-1 is closely related to lipid metabolism, and it can participate in lipid metabolism by inhibiting fat synthesis, promoting fat differentiation, enhancing cholesterol metabolism, and promoting adipose browning. GLP-1 plays a key role in the occurrence and development of metabolic diseases such as obesity, nonalcoholic fatty liver disease, and atherosclerosis by regulating lipid metabolism. It is expected to become a new target for the treatment of metabolic disorders. The effects of GLP-1 and dual agonists on lipid metabolism also provide a more complete treatment plan for metabolic diseases. This article reviews the recent research progress of GLP-1 in lipid metabolism.

Keyword

Adipose tissue; Glucagon-like peptide 1; Lipid metabolism; Non-alcoholic fatty liver disease; Obesity

Figure

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  Fig. 1. Physiological function of glucagon-like peptide-1 (GLP-1). AMPK, AMP-activated protein kinase; mTOR, mammalian target of rapamycin; TFEB, transcription factor EB; ACSL1, acyl-CoA synthetase long chain family member 1; C/EBPα, CCAAT/enhancer binding protein α; PPARγ, peroxisome proliferator-activated receptor-γ; SREBP-1c, sterol regulatory element binding protein-1c.

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  Fig. 2. Possible mechanisms by which glucagon-like peptide-1 (GLP-1) modulates liver cholesterol metabolism. (Left) In liver cells, GLP-1 can mediate cholesterol efflux by acting directly on LXRα, or by inducing an increase in ATP-binding cassette transporter A1 (ABCA1) mRNA through Ca2+/calmodulin (CaM)-dependent protein kinase kinase/CAM-dependent protein kinase IV/Prolactin regulatory element binding (CaMKK/CaMKIV/PREB), increasing apolipoprotein AI (apo AI) mRNA and promoter expression, and increasing apo AI secretion, thereby mediating intracellular cholesterol efflux. (Center) In macrophages, GLP-1 can significantly increase the expression of GLP-1 receptor through G protein-coupled receptor 119 (GPR119), enhance the activity of ABCA1, lead to the increase of apo AI, and thus promote intracellular cholesterol outflow. The expression levels of ABCA1 and ATP-binding cassette G1 (ABCG1) can also be increased by GLP-1, which inhibits the transformation process of macrophages into foam cells and reduces the level of intracellular cholesterol. (Right) GLP-1 receptor agonist (GLP-1RA) reduces cholesterol accumulation by affecting the expression of genes in the hepato-enteral circulation and cholesterol reverse transport pathway, such as farnesoid X receptor (FXR), fibroblast growth factor-15 (FGF15), fibroblast growth factor receptor 4 (FGFR4), cytochrome P450 family 7 subfamily A member 1 (Cyp7a1), proprotein convertase subtilisin/kexin type 9 (PCSK9), low-density lipoprotein receptor (LDLR), etc. T/GDCA, T/glycodeoxycholic acid; T/GLCA, T/glucoronic acid; T/GUDCA, T/glycoursodexoycholic acid; T/ GCA, T/glycocholic acid; MCA, muricholic acid; CDCA, chenodeoxycholic acid; CA, cholic acid; DCA, deoxycholic acid; LCA, lithocholicacid; UDCA, ursodeoxycholic acid; HCA, hydroxy carboxylic acid; BSH, bile salt hydrolase; CETP, cholesteryl ester transfer protein; HDL, high density lipoprotein; VLDL, very low density lipoprotein.

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  Fig. 3. Possible mechanisms by which glucagon-like peptide-1 (GLP-1) modulates the browning of white fat. (A) GLP-1 can induce fibronectin type III domain-containing protein 5 (FNDC5) expression in pancreatic β-cells through the interaction of its downstream transcription factor cAMP-response element binding protein (CREB) with binding elements in the FNDC5 promoter, thereby promoting the conversion of white adipose tissue (WAT) to brown adipose tissue (BAT). GLP-1 expression was downregulated in wild-type β Lox5 cells knocked out by FNDC5, and the induced expression of lipolysis and autophagy-related genes and proteins were also inhibited, such as adipose triacylglyceride lipase (ATGL), hormone-sensitive lipase (HSL), and hepatic lipase deficiency gene (LIPC). (B) Semaglutide, as a GLP-1 analog, can directly act on fat cells, increase the expression of thermogenic genes for browning phenotype maintenance, improve the expression of uncoupling protein 1 (UCP1), mitochondrial biosynthesis, and thermogenic marker, or promote fatty browning through nitric oxide synthase (NOS), neuropeptides (NPs), sirtuin 1 (STRT1), signal transducer and activator of transcription 3 (STAT3), and bone morphogenetic protein 4 (BMP4) signaling.

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