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Glucagon
The function of glucagon is in promoting energy release and inhibiting energy storage
in response to low circulating glucose levels, which are largely controlled by insulin [24]. Besides its role in blood–glucose regulation, patients treated with glucagon receptor an
tagonists (GRA) often suffer from dyslipidemia, fatty liver and weight gain, suggesting
that glucagon play an important role in lipid
the hepatocytes which possess the highest level of glucagon receptors. Following mecha nisms may be involved during this process: (1) At the molecular level, following glucagon
binding to its receptor on the hepatocyte, cAMP will be activated and accumulated, which
in turn activates cAMP-response element-binding protein (CREB). As a result, the tran scription of carnitine acyl transferase (CPT-1) increases, which converts fatty acids into
acylcarnitine and activates β-oxidation-increasing fatty acid catabolism [26]. In addition,
glucagon binds to the receptor and induces PKA-dependent phosphorylation, leading to
inactivation of acetyl-CoA carboxylase, which is a key enzyme in malonyl-CoA synthesis. Since malonyl-CoAs suppresses β-oxidation by inhibiting CPT-1 activity, downregulation
of malonyl-CoA will lead to more free fatty acids (FFAs) entering mitochondria for β
oxidation, rather than being released into circulation from hepatocytes in the form of VLDL
after re-esterification [27]. Under physiological conditions, glucagon is sufficient to activate
fatty acid oxidation gene expression; on the contrary, the insulin-PI3K-AKT pathway medi tates the inhibition of Foxa2 through the Thr156 site phosphorylation and nuclear exclusion
mechanism [19]. Glucagon signaling-activated adenylate cyclase (AC), on the one hand,
elevated extracellular cAMP levels, augmented the activity of peroxisome proliferator
activated receptor α (PPAR α) by direct phosphorylates AMP-activated protein kinase
(AMPK), which increased the transcription of fatty acid oxidation genes such as Aox and
Cpt1a. On the other hand, activated AMPK inhibited the transcriptional activity of SREBP1c
and ChREBP, leading to decreased lipid synthesis [28,29]. In conclusion, glucagon reduces
de novo fatty acid synthesis and thereby reduces VLDL release. Besides, it is reasonable
that glucagon signaling may increase the AMP/ATP ratio, which is required for AMP activated kinases activation. This will induce transcription of β-oxidation-related genes by
enhancing the expression of PPAR α [30]. There were in vivo experiments suggesting the
importance of glucagon in hepatic lipid metabolism. In rats and mice, chronic physiological
increased glucagon concentrations in plasma, increased mitochondrial oxidation of fat in
liver and reversed diet-induced hepatic steatosis. However, these effects were abrogated in
inositol triphosphate receptor 1(INSP3R1)-knockout mice, suggesting that the mechanisms
by which glucagon affects are also mediated by stimulation of the INSP3R1 [31]. For obese
mice, cAMP injection increased extracellular cAMP level and ameliorated the impaired
Molecules 2022, 27, 7052 5 of 20
lipid metabolism. This further confirmed the important role of cAMP-mediated PPAR α
activation through AMPK in glucagon regulation of lipid metabolism. When mice were
injected with glucagon, decreased plasma FFA, TG concentrations, hepatic TG synthesis
and secretion were observed [32].
The lipolysis of lipid droplets in adipocytes depends on PKA-dependent HSL phos
phorylation and perilipins on its surface [33], resulting in FFAs and glycerol release into
circulation eventually. Discovery of glucagon receptor mRNA in rat adipocytes [34] sup ported the effect of glucagon on HSL [34] and subsequently lipolysis [35]. The effect of
glucagon on HSL remained controversial, especially in humans; there was no evidence of
the existence of glucagon receptor expression on human adipocytes. According to the re ported literature, glucagon-induced lipolysis can be observed under the action of glucagon
with hyper-physiological concentration; however, this lipolysis can be eliminated by insulin
in some other studies [36–38], which is consistent with the powerful anti-lipolytic effects of
insulin. Therefore, if there is any such lipolysis of human adipocytes caused by glucagon, it
is physiologically significant under the premise of low insulin secretion [39–41]. Make a summary
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