Inter-Individual Variability in Lipid Response: A Narrative Review.

Lipid-lowering guidelines emphasize shared decision-making between clinicians and patients, resulting in patients anticipating the degree of response from diet or drug therapy. Challenging for physicians is understanding the sources of variability complicating their management decisions, which include non-adherence, genetic considerations, additional lipid parameters including lipoprotein (a) levels, and rare systemic responses limiting benefits that result in non-responsiveness to monoclonal antibody injection. In this narrative review, we focus on the variability of low-density lipoprotein cholesterol (LDL-C) response to guideline-directed interventions such as statins, ezetimibe, bile acid sequestrants, fibrates, proprotein/convertase subtilisin-kexin type 9 inhibitors, and LDL-C-lowering diets. We hypothesize that the variability in individual lipid responses is multifactorial. We provide an illustrative model with a check list that can be used to identify factors that may be present in the individual patient.

Ezetimibe Protects Endothelial Cells against Oxidative Stress through Akt/GSK-3ß Pathway.

Ezetimibe was reported to pharmacologically defend against oxidative stress. This study was designed to investigate whether ezetimibe can protect against the oxidative stress induced by oxidized low-density lipoprotein (oxLDL) in vitro and the underlying mechanism. Human umbilical vein endothelial cells (HUVECs) were pretreated with ezetimibe and then exposed to oxLDL for 24 h. TUNEL assay and detectionfor the protein levels of cleaved caspase-3, Bcl-xl and Bcl-2 were employed to assess the oxLDL-induced endothelial apoptosis. Intracellular reactive oxygen species (ROS) generation was evaluated by measuring dichlorofluorescein (DCF) fluorescence. The activities of endothelial antioxidant enzymes [superoxide dismutase (SOD) and catalase] were tested via an enzymatic assay. The mitochondrial membrane potential (MMP) was monitored by flow cytometry using JC-1 staining. Phosphorylation levels of glycogen synthase kinase-3p (p-GSK-3P) and Akt (p-Akt), as well as total GSK-3p and Akt were determined by Western blotting. The results showed that ezetimibe treatment inhibited HUVECs apoptosis, intracellular ROS production, and enhanced antioxidant enzyme activities elicited by oxLDL. HUVECs exposed to oxLDL alone had reduced mitochondrial function, while ezetimibe pre-intervention could significantly rescue the MMP. Furthermore, the protein levels of p-GSK-3p and p-Akt in ezetimibe-pretreated HUVECs were markedly increased as compared with those in oxLDL-induced HUVECs. However, no significant effect on total GSK- 3P and Akt was found in ezetimibe-pretreated HUVECs. Taken together, it was concluded that ezetimibe protects against oxLDL-induced oxidative stress through restoring the MMP, which may be mediated by Akt-dependent GSK-3P phosphorylation.

Ezetimibe Protects Endothelial Cells against Oxidative Stress through Akt/GSK-3β Pathway / 华中科技大学学报（医学）（英德文版）

Ezetimibe was reported to pharmacologically defend against oxidative stress.This study was designed to investigate whether ezetimibe can protect against the oxidative stress induced by oxidized low-density lipoprotein (oxLDL) in vitro and the underlying mechanism.Human umbilical vein endothelial cells (HUVECs) were pretreated with ezetimibe and then exposed to oxLDL for 24 h.TUNEL assay and detection for the protein levels of cleaved caspase-3,Bcl-xl and Bcl-2 were employed to assess the oxLDL-induced endothelial apoptosis.Intracellular reactive oxygen species (ROS) generation was evaluated by measuring dichlorofluorescein (DCF) fluorescence.The activities of endothelial antioxidant enzymes [superoxide dismutase (SOD) and catalase] were tested via an enzymatic assay.The mitochondrial membrane potential (MMP) was monitored by flow cytometry using JC-1 staining.Phosphorylation levels of glycogen synthase kinase-3β (p-GSK-3β) and Akt (p-Akt),as well as total GSK-3β and Akt were determined by Western blotting.The results showed that ezetimibe treatment inhibited HUVECs apoptosis,intracellular ROS production,and enhanced antioxidant enzyme activities elicited by oxLDL.HUVECs exposed to oxLDL alone had reduced mitochondrial function,while ezetimibe pre-intervention could significantly rescue the MMP.Furthermore,the protein levels of p-GSK-3β and p-Akt in ezetimibe-pretreated HUVECs were markedly increased as compared with those in oxLDL-induced HUVECs.However,no significant effect on total GSK-3β and Akt was found in ezetimibe-pretreated HUVECs.Taken together,it was concluded that ezetimibe protects against oxLDL-induced oxidative stress through restoring the MMP,which may be mediated by Akt-dependent GSK-3β phosphorylation.

Ezetimibe Protects Endothelial Cells against Oxidative Stress through Akt/GSK-3β Pathway / 华中科技大学学报（医学）（英德文版）

Ezetimibe was reported to pharmacologically defend against oxidative stress.This study was designed to investigate whether ezetimibe can protect against the oxidative stress induced by oxidized low-density lipoprotein (oxLDL) in vitro and the underlying mechanism.Human umbilical vein endothelial cells (HUVECs) were pretreated with ezetimibe and then exposed to oxLDL for 24 h.TUNEL assay and detection for the protein levels of cleaved caspase-3,Bcl-xl and Bcl-2 were employed to assess the oxLDL-induced endothelial apoptosis.Intracellular reactive oxygen species (ROS) generation was evaluated by measuring dichlorofluorescein (DCF) fluorescence.The activities of endothelial antioxidant enzymes [superoxide dismutase (SOD) and catalase] were tested via an enzymatic assay.The mitochondrial membrane potential (MMP) was monitored by flow cytometry using JC-1 staining.Phosphorylation levels of glycogen synthase kinase-3β (p-GSK-3β) and Akt (p-Akt),as well as total GSK-3β and Akt were determined by Western blotting.The results showed that ezetimibe treatment inhibited HUVECs apoptosis,intracellular ROS production,and enhanced antioxidant enzyme activities elicited by oxLDL.HUVECs exposed to oxLDL alone had reduced mitochondrial function,while ezetimibe pre-intervention could significantly rescue the MMP.Furthermore,the protein levels of p-GSK-3β and p-Akt in ezetimibe-pretreated HUVECs were markedly increased as compared with those in oxLDL-induced HUVECs.However,no significant effect on total GSK-3β and Akt was found in ezetimibe-pretreated HUVECs.Taken together,it was concluded that ezetimibe protects against oxLDL-induced oxidative stress through restoring the MMP,which may be mediated by Akt-dependent GSK-3β phosphorylation.