![]() An additional advantage of upregulating LXR is that ATP binding cassette subfamily A member 1 (ABCA1) would be increased, which transfers cholesterol to high-density lipoprotein (HDL) to mount reverse cholesterol transport. Cholesterol secretion into the biliary system is mediated by ATP binding cassette subfamily G member 5 (ABCG5) and ABCG8, which are regulated by liver X receptor (LXR). Increasing cholesterol excretion by the biliary system maybe a tentative strategy. Therefore, these circumstances necessitate the discovery of novel therapeutic targets and therapeutic agents to address the challenges. Also, residual inflammatory risk remains in statin-treated patients. However, some patients may experience statin intolerance and increased risk of myopathy and hyperglycemia, even overt diabetes mellitus. Statins, with good efficacy and few adverse effects, are the first-line cholesterol-lowering drugs. Therefore, different mechanisms of PCSK9 inhibition, such as siRNAs, monoclonal antibodies, and anti-sense oligonucleotides (ASOs), inhibit LDLR degradation and increase LDLR-dependent cholesterol uptake by hepatocytes, thereby reducing circulating cholesterol level. Proprotein convertase subtilisin–kexin type 9 (PCSK9) binds to and induces the degradation of LDLR. Thus, LDLR is an appealing target for LDL-C lowering. Physiologically, low-density lipoproteins (LDL) are recognized and bound by the LDL receptor (LDLR) and transported as LDL-cholesterol (LDL-C) into hepatocytes to initiate cholesterol clearance. ![]() The third category of cholesterol-lowering drugs are inhibitors of Niemann–Pick C1-like 1 (NPC1L1), such as Ezetimibe, which reduces the absorption of cholesterol by enterocytes. ![]() For example, Bempedoic acid is a prodrug which is converted into an active metabolite in the liver, then inhibits the activity of ACLY specifically in the liver (without muscle toxicity), thereby reducing acetyl-CoA-dependent cholesterol synthesis and clinically it has a good safety profile. ACLY inhibitors thus represent another class of cholesterol-lowering drugs. In addition, acetyl-CoA, the building block for cholesterol synthesis, is partially produced by ATP-citrate lyase (ACLY) from citrate. For example, β-hydroxy β-methylglutaryl-CoA (HMG-CoA) reductase (HMGCR) mediates cholesterol synthesis in the liver and serves as the primary target of statins. Cholesterol-lowering is the mainstream therapy for CVMD and several cholesterol-lowering targets have translated to clinical arena. Hypercholesterolemia represents an important risk factor for cardiovascular and metabolic diseases (CVMD). ![]()
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