Key result
The absence of gravin-mediated signaling in gravin-t/t mice significantly reduced high-fat diet-induced hyperlipidemia, aortic plaque formation, and liver damage compared to wild-type mice.
Why the study?
Gravin is known to regulate processes leading to inflammation and atherosclerosis, but its role in high-fat diet-induced atherosclerosis and hyperlipidemia remained to be investigated.
Does the absence of gravin-mediated signaling prevent high-fat diet-induced hyperlipidemia and atherosclerosis in mice?
Does the absence of gravin-mediated signaling prevent high-fat diet-induced hyperlipidemia and atherosclerosis in mice?
The absence of gravin-mediated signaling protects against high-fat diet-induced hyperlipidemia and atherosclerosis in mice, highlighting a novel regulatory pathway in lipid metabolism.
Gravin inhibition may protect against diet-induced atherosclerosis in mice; leaves open translation to human hyperlipidemia therapy.
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.
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Fan et al. (2019) studied High-fat diet-induced atherosclerosis and hyperlipidemia. gravin-t/t mutation (absence of gravin) vs. Wild-type (WT) mice was evaluated on Development of hyperlipidemia and atherosclerosis (cholesterol, triglyceride, VLDL, and aortic plaque formation). The absence of gravin-mediated signaling in gravin-t/t mice significantly reduced high-fat diet-induced hyperlipidemia, aortic plaque formation, and liver damage compared to wild-type mice.
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