Evidence for AMPK-dependent regulation of exocytosis of lipoproteins in a model liver cell line

Abstract

5'-AMP-activated kinase (AMPK) plays a key role in the regulation of cellular lipid metabolism. The contribution of vesicular exocytosis to this regulation is not known. Accordingly, we studied the effects of AMPK on exocytosis and intracellular lipid content in a model liver cell line. Activation of AMPK by metformin or 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR) increased the rates of constitutive exocytosis by about 2-fold. Stimulation of exocytosis by AMPK occurred within minutes, and persisted after overnight exposure to metformin or AICAR. Activation of AMPK also increased the amount of triacylglycerol (TG) and apolipoprotein B (apoB) secreted from lipid-loaded cells. These effects were accompanied by a decrease in the intracellular lipid content indicating that exocytosis of lipoproteins was involved in these lipid-lowering effects. While AMPK increased the rates of fatty acid oxidation (FAO), the lipid-lowering effects were quantitatively significant even after inhibition of FAO with R-etomoxir. These results suggest that hepatic AMPK stimulates constitutive exocytosis of lipoproteins, which may function in parallel with FAO to regulate intracellular lipid content.

Adenosine signaling contributes to ethanol-induced fatty liver in mice

“…AMP-activated kinase (AMPK) is a critical signaling molecule controlling hepatic fatty acid oxidation (30,31). Therefore, we determined whether adenosine receptor occupancy regulates the phosphorylation and, presumably, activation of this critical signaling enzyme.…”

“…AMPK also plays a key role in the regulation of cellular metabolism. Once activated by phosphorylation of threonine-172 or by AMP, AMPK strongly activates ACC, 3-hydroxy-3-methyl-glutaryl-CoA reductase, and other targets, leading to fatty acid oxidation and diminished cholesterol synthesis (31,(76)(77)(78). Ethanol inhibits AMPK activation, leading to accumulation of fatty acids within the hepatocyte (30).…”

<i>Ixeris dentata</i> (Thunb) Nakai Ethylacetate Extract Attenuates Sterol Regulatory Element-Binding Proteins-1c via AMP-Activated Protein Kinase Activation

“…Taken together, these observations suggest that the neuro-inflammatory responses of IDE may require the AMPK signaling pathway. Activation of AMPK leads to regulation of a number of downstream targets involved in lipid metabolism [5]. The regulation of AMPK activation and the most effective constituent in IDE need to be elaborated.…”

“…AMPK regulates cellular lipid metabolism by increasing fatty acid oxidation and constitutive lipoprotein exocytosis [5]. In the liver, activated AMPK phosphorylates and inactivates the ratelimiting enzymes of lipogenesis such as ACC, suggesting that AMPK/ACC signaling plays a critical role in hepatic lipid homeostasis [6].…”

<i>Olea europaea</i> Linn (Oleaceae) Fruit Pulp Extract Suppresses Sterol Regulatory Element-Binding Proteins-1c via AMP-Activated Protein Kinase Activation in Human Hepatic Cells

“…AMPK regulates cellular lipid metabolism by increasing fatty acid oxidation and constitutive lipoprotein exocytosis [3]. In the liver, activated AMPK phosphorylates and inactivates the ratelimiting enzymes of lipogenesis such as ACC, suggesting that AMPK/ACC signaling plays a critical role in hepatic lipid homeostasis [4].…”