The glucagon-like peptide-1 analogue exendin-4 reverses impaired intracellular Ca2 + signalling in steatotic hepatocytes

• Exendin-4 reverses lipid-induced inhibition of Ca2 + entry in steatotic liver cells.
• Mechanism involves GLP-1 receptors, cyclic AMP, PKA and rapid lipolysis.
• Activation of Ca2 + entry may provide a new strategy for liver lipid reduction.

The release of Ca2 + from the endoplasmic reticulum (ER) and subsequent replenishment of ER Ca2 + by Ca2 + entry through store-operated Ca2 + channels (SOCE) play critical roles in the regulation of liver metabolism by adrenaline, glucagon and other hormones. Both ER Ca2 + release and Ca2 + entry are severely inhibited in steatotic hepatocytes. Exendin-4, a slowly-metabolised glucagon-like peptide-1 (GLP-1) analogue, is known to reduce liver glucose output and liver lipid, but the mechanisms involved are not well understood. The aim of this study was to determine whether exendin-4 alters intracellular Ca2 + homeostasis in steatotic hepatocytes, and to evaluate the mechanisms involved. Exendin-4 completely reversed lipid-induced inhibition of SOCE in steatotic liver cells, but did not reverse lipid-induced inhibition of ER Ca2 + release. The action of exendin-4 on Ca2 + entry was rapid in onset and was mimicked by GLP-1 or dibutyryl cyclic AMP. In steatotic liver cells, exendin-4 caused a rapid decrease in lipid (half time 6.5 min), inhibited the accumulation of lipid in liver cells incubated in the presence of palmitate plus the SOCE inhibitor BTP-2, and enhanced the formation of cyclic AMP. Hormone-stimulated accumulation of extracellular glucose in glycogen replete steatotic liver cells was inhibited compared to that in non-steatotic cells, and this effect of lipid was reversed by exendin-4. It is concluded that, in steatotic hepatocytes, exendin-4 reverses the lipid-induced inhibition of SOCE leading to restoration of hormone-regulated cytoplasmic Ca2 + signalling. The mechanism may involve GLP-1 receptors, cyclic AMP, lipolysis, decreased diacylglycerol and decreased activity of protein kinase C.

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