Absence of gravin-mediated signaling inhibits development of high-fat diet-induced hyperlipidemia and atherosclerosis

Abstract

Gravin, an A-kinase anchoring protein, is known to play a role in regulating key processes that lead to inflammation and atherosclerosis development, namely, cell migration, proliferation, and apoptosis. We investigated the role of gravin in the development of high-fat diet (HFD)-induced atherosclerosis and hyperlipidemia. Five-week-old male wild-type (WT) and gravin-t/t mice were fed a normal diet or an HFD for 16 wk. Gravin-t/t mice showed significantly lower liver-to-body-weight ratio, cholesterol, triglyceride, and very low-density lipoprotein levels in serum as compared with WT mice on HFD. Furthermore, there was less aortic plaque formation coupled with decreased lipid accumulation and liver damage, as the gravin-t/t mice had lower levels of serum alanine aminotransferase and aspartate aminotransferase. Additionally, gravin-t/t HFD-fed mice had decreased expression of liver 3-hydroxy-3-methyl-glutaryl-CoA reductase, an essential enzyme for cholesterol synthesis and lower fatty acid synthase expression. Gravin-t/t HFD-fed mice also exhibited inhibition of sterol regulatory element binding protein-2 (SREBP-2) expression, a liver transcription factor associated with the regulation of lipid transportation. In response to platelet-derived growth factor receptor treatment, gravin-t/t vascular smooth muscle cells exhibited lower intracellular calcium transients and decreased protein kinase A- and protein kinase C-dependent substrate phosphorylation, notably involving the Erk1/2 signaling pathway. Collectively, these results suggest the involvement of gravin-dependent regulation of lipid metabolism via the reduction of SREBP-2 expression. The absence of gravin-mediated signaling lowers blood pressure, reduces plaque formation in the aorta, and decreases lipid accumulation and damage in the liver of HFD mice. Through these processes, the absence of gravin-mediated signaling complex delays the HFD-induced hyperlipidemia and atherosclerosis. NEW & NOTEWORTHY The gravin scaffolding protein plays a key role in the multiple enzymatic pathways of lipid metabolism. We have shown for the first time the novel role of gravin in regulating the pathways related to the initiation and progression of atherosclerosis. Specifically, an absence of gravin-mediated signaling decreases the lipid levels (cholesterol, triglyceride, and VLDL) that are associated with sterol regulatory element binding protein-2 downregulation.

Proteomics analysis of adipose depots after intermittent fasting reveals visceral fat preservation mechanisms

“…This suggests that AKAP12 contributes to the decreased lipolytic activity seen in our EODF model and may have an association with ADRB3 signaling. Indeed, AKAP12 has been studied previously in the context of cardiomyocytes, where it has been reported to bind to the b2adrenergic receptor (ADRB2) and PKA, functionally coupling the receptor to downstream signaling pathways, which were Cell Reports 34, 108804, March 2, 2021 11 Resource ll reduced greatly in AKAP12 knockout mice (Fan et al, 2019;Guillory et al, 2013;Rababa'h et al, 2014). We suggest that AKAP12 may play a role in ADRB3 signaling in adipose tissue and that its downregulation after EODF in vWAT would contribute to the reduction in lipolytic potential.…”

Liraglutide improves lipid metabolism by enhancing cholesterol efflux associated with ABCA1 and ERK1/2 pathway

“…We next examined the possible involvement of MAPK/ERK1/2 pathway in liraglutide-induced ABCA1 expression. ERK1/2 is one member of MAPKKs family, which is an important kinase involved in many kinds of biological physiological process [30, 31]. Therefore, we investigated whether liraglutide could stimulate intracellular ERK1/2 phosphorylation events.…”

High-Fat Diets-Induced Metabolic Disorders to Study Molecular Mechanism of Hyperlipidemia in Rats

“…Maulana & Ridwan administration of HFD, the feedback regulation ability slowly decrease and is harmful to the body, especially to the heart and liver (24). Long-term HFD feeding can have a direct or indirect impact on lipid metabolism (9,25). HFD can also lead to insulin resistance, which disturbs glucose homeostasis and indirectly affects lipid metabolism disorders (26,27).…”