Constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are closely related nuclear receptors with overlapping regulatory functions in xenobiotic clearance but distinct roles in endobiotic metabolism. Car activation has been demonstrated to ameliorate hypercholesterolemia by regulating cholesterol metabolism and bile acid elimination, whereas PXR activation is associated with hypercholesterolemia and liver steatosis. Here we show a human CAR agonist/PXR antagonist, MI-883, which effectively regulates genes related to xenobiotic metabolism and cholesterol/bile acid homeostasis by leveraging CAR and PXR interactions in gene regulation. Through comprehensive analyses utilizing lipidomics, bile acid metabolomics, and transcriptomics in humanized PXR-CAR-CYP3A4/3A7 mice fed high-fat and high-cholesterol diets, we demonstrate that MI-883 significantly reduces plasma cholesterol levels and enhances fecal bile acid excretion. This work paves the way for the development of ligands targeting multiple xenobiotic nuclear receptors. Such ligands hold the potential for precise modulation of liver metabolism, offering new therapeutic strategies for metabolic disorders.
- MeSH
- Cholesterol * metabolism blood MeSH
- Cytochrome P-450 CYP3A metabolism genetics MeSH
- Diet, High-Fat * adverse effects MeSH
- Hypercholesterolemia * drug therapy metabolism MeSH
- Hypolipidemic Agents pharmacology therapeutic use MeSH
- Liver metabolism drug effects MeSH
- Constitutive Androstane Receptor * MeSH
- Humans MeSH
- Lipid Metabolism drug effects MeSH
- Disease Models, Animal MeSH
- Mice, Inbred C57BL MeSH
- Mice MeSH
- Pregnane X Receptor * metabolism genetics MeSH
- Pyridines MeSH
- Receptors, Cytoplasmic and Nuclear * metabolism agonists genetics MeSH
- Gene Expression Regulation drug effects MeSH
- Bile Acids and Salts * metabolism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Východisko: Lipoproteinová aferéza (LA) je velmi účinná, časově náročná a nákladná metoda snižování hladin LDL-cholesterolu (Low Denzity Lipoprotein Cholesterol – LDL-C), lipoproteinu(a) – Lp(a) a dalších apoB obsahujících lipoproteinů, včetně na triglyceridy bohatých lipoproteinů. Tato metoda byla poprvé použita téměř před 50 lety a dlouho byla terapií „poslední možnosti“ pro dyslipidemie, které jinak nelze řešit. V posledních letech jsou vyvíjena nová, velmi účinná hypolipidemika a účelem tohoto přehledu je definovat roli lipoproteinové aferézy v současném kontextu. Rozbor problematiky: Lipoproteinová aferéza stále hraje důležitou roli v léčbě pacientů s homozygotní familiární hypercholesterolemií (HoFH) a některých pacientů s dalšími formami hypercholesterolemie a aterosklerotickými kardiovaskulárními chorobami (ASKVO). Zejména pacienti, kteří nedosahují léčebných cílů navzdory moderní hypolipidemické farmakoterapii, ať už proto, že ji netolerují nebo je terapeutická odpověď nedostatečná. Lp(a) je vedle LDL-C další důležitý kardiovaskulární rizikový faktor a lipoproteinová aferéza je taktéž využívána ke snížení koncentrací lipoproteinu(a) u pacientů s významným zvýšením Lp(a) a kardiovaskulárním onemocněním. Existuje však značná heterogenita v doporučeních vědeckých autorit ohledně toho, které skupiny pacientů by měly být léčeny lipoproteinovou aferézou. Závěr: Doporučení odborných společností indikují léčbu klasickými i moderními hypolipidemiky před zahájením léčby lipoproteinovou aferézou a současně také s aferézou s cílem snížení a dosažení cílových hladin LDL-C. LA nemusí předcházet farmakoterapii, naopak klinické studie ukázaly možnost weaningu z LA při použití testovaných nových léčiv. Kombinované použití lipoproteinové aferézy a nových hypolipidemik (inhibitorů PCSK9, lomitapidu a evinakumabu) nabízí cenný terapeutický přístup u pacientů s obtížně kontrolovatelnými hladinami LDL-C. Lipoproteinová aferéza zůstává důležitým nástrojem pro terapii pacientů se závažnými dyslipidemiemi rezistentními na léčbu, zejména pacientů s homozygotní FH.
Background: Lipoprotein apheresis (LA) is a very effective, time-consuming and costly method of lowering low-density lipoprotein cholesterol (LDL-C), lipoprotein(a) – Lp(a) and other apoB-containing lipoproteins, including triglyceride-rich lipoproteins. This method was first used almost 50 years ago and has long been a “last resort” therapy for dyslipidemias that cannot otherwise be addressed. In recent years, new, highly effective hypolipidemic agents have been developed and the purpose of this review is to define the role of lipoprotein apheresis in the current context. Discussion of the problem: Lipoprotein apheresis still plays an important role in the treatment of patients with homozygous familial hypercholesterolemia (HoFH) and some patients with other forms of hypercholesterolemia and atherosclerotic cardiovascular disease (ASCVD). In particular, patients who fail to achieve therapeutic goals despite modern hypolipidemic drug therapy, either because they are intolerant or the therapeutic response is inadequate. Lp(a) is another important cardiovascular risk factor besides LDL-C, and lipoprotein apheresis is also used to reduce lipoprotein(a) concentrations in patients with significant elevations of Lp(a) and cardiovascular disease. However, there is considerable heterogeneity in the recommendations of scientific authorities regarding which groups of patients should be treated with lipoprotein apheresis. Conclusion. Recommendations of professional societies indicate treatment with conventional and modern hypolipidemic agents before starting lipoprotein apheresis therapy and simultaneously with apheresis to reduce and achieve target LDL-C levels. LA does not need to precede drug therapy; on the contrary, clinical trials have shown the possibility of weaning from LA when using investigational new drugs. The combined use of lipoprotein apheresis and novel hypolipidemics (PCSK9 inhibitors, lomitapide and evinacumab) offers a valuable therapeutic approach for patients with difficult-to-control LDL-C levels. Lipoprotein apheresis remains an important tool for the treatment of patients with severe treatment-resistant dyslipidemias, especially those with homozygous FH.
- Keywords
- lipoproteinová aferéza,
- MeSH
- Atherosclerosis therapy MeSH
- Dyslipidemias * therapy MeSH
- Antibodies, Monoclonal, Humanized administration & dosage MeSH
- Hypercholesterolemia therapy MeSH
- Hypolipidemic Agents administration & dosage pharmacology MeSH
- Cardiovascular Diseases therapy MeSH
- Cholesterol, LDL blood drug effects MeSH
- Humans MeSH
- Lipoprotein(a) blood drug effects MeSH
- PCSK9 Inhibitors therapeutic use MeSH
- Heart Disease Risk Factors MeSH
- Blood Component Removal * methods instrumentation MeSH
- Check Tag
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
- MeSH
- Phytotherapy MeSH
- Hypercholesterolemia * diet therapy therapy MeSH
- Humans MeSH
- Check Tag
- Humans MeSH
- MeSH
- Early Diagnosis MeSH
- Hypercholesterolemia * diagnosis drug therapy genetics prevention & control MeSH
- Humans MeSH
- Lipoprotein(a) adverse effects MeSH
- Neonatal Screening MeSH
- Primary Prevention MeSH
- Heart Disease Risk Factors MeSH
- Secondary Prevention MeSH
- Health Education MeSH
- Check Tag
- Humans MeSH
- Publication type
- Newspaper Article MeSH
- MeSH
- Dyslipidemias * drug therapy MeSH
- Hypercholesterolemia drug therapy MeSH
- Congresses as Topic MeSH
- Cholesterol, LDL analysis MeSH
- Humans MeSH
- Check Tag
- Humans MeSH
- Publication type
- News MeSH
- Geographicals
- Czech Republic MeSH
- Keywords
- projekt MUNI,
- MeSH
- Phytotherapy methods MeSH
- Hypercholesterolemia therapy MeSH
- Hyperemesis Gravidarum therapy MeSH
- Motion Sickness therapy MeSH
- Humans MeSH
- Rhizome MeSH
- Plant Preparations therapeutic use MeSH
- Zingiber officinale * immunology metabolism MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Keywords
- alirokumab, evolokumab,
- MeSH
- Biological Therapy MeSH
- Hypercholesterolemia * drug therapy classification MeSH
- Hypolipidemic Agents pharmacology MeSH
- Injections, Subcutaneous MeSH
- Cholesterol, LDL adverse effects MeSH
- Humans MeSH
- PCSK9 Inhibitors * pharmacology therapeutic use MeSH
- Insurance, Health, Reimbursement MeSH
- Treatment Outcome MeSH
- Check Tag
- Humans MeSH
- MeSH
- Atherosclerosis drug therapy complications pathology prevention & control MeSH
- Stroke drug therapy prevention & control MeSH
- Diabetes Mellitus, Type 2 drug therapy complications MeSH
- Hypercholesterolemia drug therapy blood MeSH
- Hypolipidemic Agents economics therapeutic use MeSH
- Cardiovascular Diseases drug therapy complications prevention & control MeSH
- Clinical Studies as Topic MeSH
- Cholesterol, LDL * blood drug effects MeSH
- Humans MeSH
- RNA, Small Interfering economics therapeutic use MeSH
- Secondary Prevention methods MeSH
- Check Tag
- Humans MeSH
- Publication type
- Newspaper Article MeSH
