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The Biochemical Journal May 2023Mitochondrial β-oxidation is the most prominent pathway for fatty acid oxidation but alternative oxidative metabolism exists. Fatty acid ω-oxidation is one of these... (Review)
Review
Mitochondrial β-oxidation is the most prominent pathway for fatty acid oxidation but alternative oxidative metabolism exists. Fatty acid ω-oxidation is one of these pathways and forms dicarboxylic acids as products. These dicarboxylic acids are metabolized through peroxisomal β-oxidation representing an alternative pathway, which could potentially limit the toxic effects of fatty acid accumulation. Although dicarboxylic acid metabolism is highly active in liver and kidney, its role in physiology has not been explored in depth. In this review, we summarize the biochemical mechanism of the formation and degradation of dicarboxylic acids through ω- and β-oxidation, respectively. We will discuss the role of dicarboxylic acids in different (patho)physiological states with a particular focus on the role of the intermediates and products generated through peroxisomal β-oxidation. This review is expected to increase the understanding of dicarboxylic acid metabolism and spark future research.
Topics: Microbodies; Fatty Acids; Oxidation-Reduction; Mitochondria; Liver; Dicarboxylic Acids
PubMed: 37140888
DOI: 10.1042/BCJ20230041 -
The New England Journal of Medicine Apr 2023
Topics: Humans; Cardiovascular Diseases; Dicarboxylic Acids; Fatty Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents
PubMed: 36876758
DOI: 10.1056/NEJMe2300793 -
Drugs May 2020Bempedoic acid is a non-statin antihyperlipidaemic drug being developed by Esperion Therapeutics for the treatment of hypercholesterolaemia. Based on positive findings... (Review)
Review
Bempedoic acid is a non-statin antihyperlipidaemic drug being developed by Esperion Therapeutics for the treatment of hypercholesterolaemia. Based on positive findings in the phase III CLEAR clinical trial programme, bempedoic acid has been approved in the USA and in the EU as monotherapy (NEXLETOL in the USA, Nilemdo in the EU) and as a fixed-dose combination with ezetimibe (NEXLIZET in the USA, Nustendi in the EU). This article summarizes the milestones in the development of bempedoic acid leading to these first approvals.
Topics: Dicarboxylic Acids; Drug Approval; Fatty Acids; Humans; Hypercholesterolemia; Hypolipidemic Agents; Molecular Structure
PubMed: 32314225
DOI: 10.1007/s40265-020-01308-w -
American Family Physician Jun 2024Rosacea is a chronic inflammatory skin disease of the central face, affecting 5% of the population. The exact etiology is unknown. A diagnosis is made based on the... (Review)
Review
Rosacea is a chronic inflammatory skin disease of the central face, affecting 5% of the population. The exact etiology is unknown. A diagnosis is made based on the updated 2017 National Rosacea Society Expert Committee guidelines, including fixed erythema, phymatous changes of skin thickening due to sebaceous gland hyperplasia and fibrosis, papules, pustules, telangiectasia, and flushing. Delays in an accurate diagnosis and treatment may occur in skin of color due to difficulty visualizing erythema and telangiectasia. The daily use of sunscreen, moisturizers, and mild skin cleansers and avoidance of triggers are essential aspects of maintenance treatment. Effective topical treatment options include alpha-adrenergic receptor agonists for flushing and ivermectin, metronidazole, and azelaic acid for papules and pustules. Systemic treatments include nonselective beta blockers for flushing, low-dose doxycycline, and isotretinoin for papules and pustules. Rosacea can significantly affect a patient's emotional health and quality of life. A referral for care is recommended for fixed phymatous changes and ocular rosacea. (Am Fam Physician. 2024;109(6):533-542.
Topics: Rosacea; Humans; Dermatologic Agents; Quality of Life; Dicarboxylic Acids
PubMed: 38905551
DOI: No ID Found -
Drug and Therapeutics Bulletin Nov 2023Nissen SE, Lincoff AM, Brennan D, et al. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. 2023;388:1353-64.
Nissen SE, Lincoff AM, Brennan D, et al. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. 2023;388:1353-64.
Topics: Humans; Dicarboxylic Acids; Fatty Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Cardiovascular Diseases
PubMed: 37833039
DOI: 10.1136/dtb.2023.000054 -
Atherosclerosis Mar 2021
Topics: Atorvastatin; Dicarboxylic Acids; Ezetimibe; Fatty Acids; Humans; Hypercholesterolemia
PubMed: 33482997
DOI: 10.1016/j.atherosclerosis.2021.01.009 -
Journal of the American Society of... Feb 2024In this study, we demonstrate that a common, low-cost compound known as octanedioic acid (DC 8 ) can protect mice from kidney damage typically caused by...
SIGNIFICANCE STATEMENT
In this study, we demonstrate that a common, low-cost compound known as octanedioic acid (DC 8 ) can protect mice from kidney damage typically caused by ischemia-reperfusion injury or the chemotherapy drug cisplatin. This compound seems to enhance peroxisomal activity, which is responsible for breaking down fats, without adversely affecting mitochondrial function. DC 8 is not only affordable and easy to administer but also effective. These encouraging findings suggest that DC 8 could potentially be used to assist patients who are at risk of experiencing this type of kidney damage.
BACKGROUND
Proximal tubules are rich in peroxisomes, which are damaged during AKI. Previous studies demonstrated that increasing peroxisomal fatty acid oxidation (FAO) is renoprotective, but no therapy has emerged to leverage this mechanism.
METHODS
Mice were fed with either a control diet or a diet enriched with dicarboxylic acids, which are peroxisome-specific FAO substrates, then subjected to either ischemia-reperfusion injury-AKI or cisplatin-AKI models. Biochemical, histologic, genetic, and proteomic analyses were performed.
RESULTS
Both octanedioic acid (DC 8 ) and dodecanedioic acid (DC 12 ) prevented the rise of AKI markers in mice that were exposed to renal injury. Proteomics analysis demonstrated that DC 8 preserved the peroxisomal and mitochondrial proteomes while inducing extensive remodeling of the lysine succinylome. This latter finding indicates that DC 8 is chain shortened to the anaplerotic substrate succinate and that peroxisomal FAO was increased by DC 8 .
CONCLUSIONS
DC 8 supplementation protects kidney mitochondria and peroxisomes and increases peroxisomal FAO, thereby protecting against AKI.
Topics: Animals; Humans; Mice; Acute Kidney Injury; Cisplatin; Dicarboxylic Acids; Dietary Supplements; Fatty Acids; Proteomics; Reperfusion Injury
PubMed: 38044490
DOI: 10.1681/ASN.0000000000000266 -
Journal of Cardiovascular Pharmacology Oct 2020Statins remain the preferred agent to reduce low-density lipoprotein cholesterol (LDL-C) and lower atherosclerotic cardiovascular disease (ASCVD) risk. Additional... (Review)
Review
Statins remain the preferred agent to reduce low-density lipoprotein cholesterol (LDL-C) and lower atherosclerotic cardiovascular disease (ASCVD) risk. Additional nonstatin agents are recommended to further lower LDL-C among patients at high-risk of ASCVD or those with heterozygous familial hypercholesterolemia, despite statin therapy. Patients unable to tolerate recommended doses of statin therapy due to adverse effects, including statin-associated muscle symptoms, may also require additional nonstatin agents to lower LDL-C and ASCVD risk. Bempedoic acid is a first-in-class, once-daily oral agent, recently approved as monotherapy and in combination with ezetimibe, as an adjunct to maximally tolerated statin therapy in patients with ASCVD or heterozygous familial hypercholesterolemia who require additional LDL-C lowering. Its novel mechanism is reported to avoid adverse muscle symptoms associated with statins. The effectiveness and safety of bempedoic acid and bempedoic acid/ezetimibe combination have been reported in multiple phase 2 and 3 trials. In this review, we report the lipid-lowering effects associated with bempedoic acid, and the safety profile from multiple clinical trials. Based on available data, bempedoic acid significantly lowers LDL-C and other atherogenic lipoprotein measures, and high-sensitivity C-reactive protein when added to background lipid-lowering therapy in patients with and without statin intolerance. Overall safety of bempedoic acid seems to be comparable to placebo, except for increased serum uric acid and tendon rupture. Ongoing clinical trials assessing the long-term safety and cardiovascular outcomes will provide additional insight into the role of bempedoic acid as an adjunct lipid-lowering medication.
Topics: Animals; Anticholesteremic Agents; Biomarkers; Cardiovascular Diseases; Cholesterol, LDL; Dicarboxylic Acids; Down-Regulation; Dyslipidemias; Fatty Acids; Humans; Risk Assessment; Risk Factors; Treatment Outcome
PubMed: 32732494
DOI: 10.1097/FJC.0000000000000887 -
Clinical and Experimental Dermatology Feb 2022Acne and rosacea are common inflammatory skin conditions present in numerous racial and ethnic groups. There are distinct differences in clinical presentation,... (Review)
Review
Acne and rosacea are common inflammatory skin conditions present in numerous racial and ethnic groups. There are distinct differences in clinical presentation, exacerbating factors, potential triggers and consequences of both conditions in individuals with skin of colour (SOC), classified as Fitzpatrick skin types III-VI. For example, acne can be complicated by the development of postinflammatory hyperpigmentation and keloid scarring in SOC, and this can influence treatment choice. Although rosacea is reported less frequently in SOC, this may be the result of delayed diagnosis or late presentation due to the difficulty in discerning the classic features of erythema in darker skin tones. In such cases, additional clues in the medical history and clinical examination may assist in making the diagnosis. This review aims to summarize nuances in both the diagnosis and management of these two common skin conditions in patients with SOC to support clinicians in providing an individualized treatment approach.
Topics: Acne Vulgaris; Adapalene; Diagnosis, Differential; Dicarboxylic Acids; Humans; Racial Groups; Rosacea; Skin Pigmentation; Tretinoin
PubMed: 34709676
DOI: 10.1111/ced.14994 -
Current Atherosclerosis Reports Mar 2024Bempedoic acid is a novel therapeutic agent that is designed to reduce levels of low-density lipoprotein cholesterol (LDL-C). The purpose of this review is to provide... (Review)
Review
PURPOSE OF REVIEW
Bempedoic acid is a novel therapeutic agent that is designed to reduce levels of low-density lipoprotein cholesterol (LDL-C). The purpose of this review is to provide the background for development of bempedoic acid, findings from clinical trials and to discuss clinical implications.
RECENT FINDINGS
Bempedoic acid inhibits ATP citrate lyase within the liver and reduces cholesterol synthesis, with the potential to avoid muscle symptoms experienced by patients treated with statins. Early clinical studies demonstrated that administration of bempedoic acid resulted in lowering of LDL-C by 20-30% as monotherapy and by 40-50% when combined with ezetimibe, in addition to lowering of high sensitivity C-reactive protein by 20-30%. The CLEAR Outcomes trial of high cardiovascular risk patients, with elevated LDL-C levels and either unable or unwilling to take statins demonstrated that bempedoic acid reduced the rate of major adverse cardiovascular events. A greater incidence of elevation of hepatic transaminase and creatinine, gout, and cholelithiasis were consistently observed in bempedoic acid-treated patients. Bempedoic acid presents an additional therapeutic option to achieve more effective lowering of LDL-C levels and reduction in cardiovascular risk.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Cholesterol, LDL; Fatty Acids; Dicarboxylic Acids
PubMed: 38294660
DOI: 10.1007/s11883-024-01188-5