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  • br Cholesterol handling in the arterial wall cells Foam cell


    Cholesterol handling in the arterial wall cells Foam cell formation in the arterial intima is a major hallmark of early-stage atherosclerotic lesions, which is attributed to uncontrolled uptake of modified lipoproteins, excess cholesterol esterification and impaired cholesterol release [44]. As a critical component in atherosclerotic lesions, macrophages have long been considered as the main source of foam mm molarity [45]. During atherogenesis, circulating monocytes transmigrate into the intima of the arterial wall where they differentiate into macrophages and then take up a large number of modified lipoprotein particles [46]. Lipid accumulation promotes the transformation of macrophages into foam cells. Other cell types such as vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) also contribute to the formation of foam cells.
    Cholesterol uptake by the liver
    Cholesterol excretion As mentioned above, excessive cholesterol accumulation is an independent risk factor of CVD. Since cholesterol can not be degraded in cells, excessive cholesterol must be eliminated from the body to avoid hypercholesterolemia and atherosclerosis. Cholesterol excretion is considered to be the final step of RCT, and this process can occur via two routes: ABCG5/G8-mediated hepatobiliary secretion and TICE [346].
    The therapeutic strategies to promote the CTS CVD accounts for >17 million deaths globally every year, and this figure is predicted to rise to >23 million by 2030 [397]. Dyslipidemia, in particular hypercholesterolemia, is considered to be a major risk factor for CVD. Statins, the cornerstone for the primary and secondary prevention of CVD, have a potent hypolipidemic effect by inhibiting HMG-CoA reductase and upregulating hepatic LDLR expression [398,399]. However, a recent study showed that statins do not reduce endogenous cholesterol synthesis due to a compensatory increase in HMG-CoA reductase levels in vivo, but elevate the number of LDLR at the surface of hepatocytes [400]. A higher residual cardiovascular risk is also observed in statin-treated patients [401]. These findings highlight an urgent need for non-statin therapies. A number of drugs targeting the CTS are currently available. They can be used either in monotherapy or combination with statins (Table 1).
    Conclusion and future directions The CTS containing other major steps in addition to the traditional RCT pathway is a working model proposed to reflect overall cholesterol transport and metabolism. This model has expanded our understanding of body cholesterol metabolism and more precisely revealed the relationship between hypercholesterolemia and atherosclerosis based on the recent developments in the field. A number of critical agents that regulate the CTS have become the developmental targets for the prevention and treatment of CVD. Undoubtedly, there are many outstanding questions that need to be addressed. As discussed above, cholesterol efflux from peripheral cells like macrophages, the first step of RCT, is a critical determinant of atherosclerosis, but a recent study showed that overall cholesterol homeostasis might be directly irrelevant to atherosclerosis [524]. There is, therefore, a great need for additional research to precisely define the role of the CTS in atherogenesis. HDL plays a crucial role in the CTS process and has long been thought to be an atheroprotective factor. The first step of HDL biogenesis is that apoA-I passes through the endothelial cell layer that forms the barrier between the intima and the plasma. F0F1 ATPase has been shown to promote transendothelial migration of apoA-I [525]. However, cellular signaling pathways activated by the interaction of F0F1 ATPase with apoA-I remain unclear. The molecular mechanisms responsible for HDL egress from the intima to the bloodstream are also poorly understood. Elucidation of the mechanisms and identification of genetic polymorphisms associated with variations in intimal HDL biogenesis will be greatly helpful for developing novel HDL-directed therapies. Further, how is NPC1L1 recycled to plasma membrane once it releases the bound cholesterol in the ERC? How can we establish standard quantitative methods to detect HDL functions and TICE in humans? What is the trafficking itinerary of TICE-derived cholesterol after entering enterocytes? Answering these questions will enhance insightful knowledge about the underlying mechanisms for the CTS and may provide novel pathways for the development of therapeutics to improve clinical outcomes of CVD patients.