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Dyslipidemia
Published in Jahangir Moini, Matthew Adams, Anthony LoGalbo, Complications of Diabetes Mellitus, 2022
Jahangir Moini, Matthew Adams, Anthony LoGalbo
There are dietary supplements that lower LDL, including fiber, margarines, and other products that contain the plant sterols called campesterol and sitosterol, or that contain stanols. Fiber supplements reduce cholesterol by decreasing its absorption and increasing its excretion. The fiber supplements based on oats can provide up to 18% total cholesterol decrease. The plant sterols and stanols displace cholesterol from the intestinal micelles, and may reduce LDL by up to 10%, with no effect upon HDL or total triglycerides. For homozygous familial hypercholesterolemia, medications include lomitapide and mipomersen. Lomitapide inhibitors the microsomal triglyceride transfer protein that interfere with secretion of total triglycerides rich lipoproteins in the intestine and liver. Doses start low and are titrated gradually, every 2 weeks. The patient must eat a diet with fewer than 20% of calories from fat. Adverse effects of lomitapide include diarrhea, elevated liver enzymes, and increased fat in the liver. Mipomersen is an apo B antisense oligonucleotide. It decreases apo B synthesis in the liver, while decreasing levels of LDL, apo B, and Lp(α). Mipomersen is injected subcutaneously. Adverse effects include injection site reactions, increased fat in the liver, enzyme elevations, and flu-like symptoms.
Enzyme Kinetics and Drugs as Enzyme Inhibitors
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Lomitapide selectively inhibits the microsomal triglyceride transfer protein (MTP) located in the ER of hepatocytes and enterocytes where it is responsible for transferring triglycerides, cholesterolesters, and phospholipids onto newly synthesized plasma lipoproteins associated Apo B leading to the formation of VLDL, IDL, LDL, chylomicrons. Inhibition of MTP results in a reduction of chylomicrons secretionintheintestineandthatof VLDL in the liver which leads to decreased levels of LDL, apolipoprotein B, triglycerides, non-HDL cholesterol, and Lp(a). Lomitapide causes side effects in the gastrointestinal tract (diarrhea, nausea, vomiting) and in the liver, where the reduction of VLDL production goes along with fatty liver formation and enhanced liver enzymes (Feingold and Grunfeld, 2016, and literature cited therein).
Mechanism of Action of Isotretinoin
Published in Ayse Serap Karadag, Berna Aksoy, Lawrence Charles Parish, Retinoids in Dermatology, 2019
Triglyceride loading to apoB-100 is facilitated by microsomal triglyceride transfer protein (MTP), which is activated by FoxO1 (129,130). Each VLDL molecule contains one apoB-100, which is required for triglyceride loading onto the VLDL particle. ApoB-100 and apoB-48 are created by a premature stop codon by apoB mRNA-editing enzyme complex 1 (apobec1).
Circadian control of Nocturnin and its regulatory role in health and disease
Published in Chronobiology International, 2023
Shruti Kulshrestha, Ranjitsinh Devkar
Research reports provide growing body of evidence on the role of Noct in regulating intestinal absorption and trafficking of biomolecules (Douris et al. 2011). The enterocytes present in the luminal lining of the intestine uptake fatty acids (FAs) and convert them into neutral TGs that are either stored as cytoplasmic lipid droplets (CLDs) or converted to chylomicrons (CMs) that are released in blood circulation (Demignot et al. 2014). The Noct KO mice were reportedly resistant to diet-induced obesity and the same was attributed to a greater sequestration of TGs in CLDs with deficits in CM synthesis. This study had also been extended to the isolated enterocytes from Noct KO mice that had shown disrupted lipid trafficking as evidenced by studies with radiolabelled FAs. Another attribute found in these enterocytes includes intracellular accumulation of CM particles (Figure 2) (Douris et al. 2011). However, the higher activity levels of microsomal triglyceride transfer protein (MTP) were thought to be a compensatory response to the intracellular TG accumulation.
Advances with lipid-lowering drugs for pediatric patients with familial hypercholesterolemia
Published in Expert Opinion on Pharmacotherapy, 2021
Filipe Ferrari, Vítor M. Martins, Viviane Z. Rocha, Raul D. Santos
Lomitapide reduces circulating LDL concentrations indirectly by inhibiting the microsomal triglyceride transfer protein (MTP) that acts upon binding triglyceride molecules to apolipoprotein B-100 in the liver [77]. Therefore, lomitapide reduces the production of LDL predecessors, very-low-density- (VLDL), and intermediate-density (IDL) lipoproteins. Lomitapide is approved for adults with homozygous FH only and its use may be limited by gastrointestinal adverse events and liver fat accumulation. However, lomitapide has been used in a compassionate form in a small number of pediatric homozygous FH patients [10,67]. In a series of 11 pediatric cases (mean age 11.6 ± 1.1 years) lomitapide reduced LDL-C by a mean 58.4% after a mean 20-month follow-up [10]. Most adverse events were gastrointestinal.
Long non-coding RNA NEAT1 promotes steatosis via enhancement of estrogen receptor alpha-mediated AQP7 expression in HepG2 cells
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2019
Xiaohua Fu, Jing Zhu, Lin Zhang, Jing Shu
Non-alcoholic fatty liver disease (NAFLD), characterized as the excessive hepatic lipid accumulation, is found to closely bridge with a substantial increased risk of diabetes mellitus, dyslipidemia and cardiovascular disease [1]. The current theory of “two-hit” explained the pathogenesis and progression of NAFLD [2]. Initially, the overmuch fatty acids from peripheral adipose tissue or local synthesis and the accompanying insulin resistance-mediated triglycerides (TG) are stored in liver. Then, the microsomal triglyceride transfer protein (MTP) plays a crucial role in assembly and secretion of hepatic triglyceride as very low-density lipoprotein for steatosis and fibrosis. The second hit is derived from oxidative stress and excessive cytokine production. The enhancement of the mitochondrial β oxidation, reactive oxygen species and the oxidative stress cascade, as well as cytokines such as tumour necrosis factor-α (TNF-α), adiponectin [3] modulated by the free fatty acids, are all important in the pathogenesis of NAFLD.