Itaconate stabilizes CPT1a to enhance lipid utilization during inflammation
Rabina Mainali1, Nancy Buechler1, Cristian Otero1
1Department of Pathology, Section on Comparative Medicine, Wake Forest School of Medicine, Winston Salem, United States.
Elife
|February 2, 2024
Summary
Itaconate, an inflammation-linked metabolite, plays a key role in managing lipid metabolism during sepsis. Its deficiency in Acod1 knockout mice leads to hepatic steatosis and altered fuel utilization, highlighting its systemic importance.
Area of Science:
- Immunometabolism
- Molecular Biology
- Sepsis Pathophysiology
Background:
- Inflammation redirects TCA cycle intermediates to produce itaconate, an immunomodulatory metabolite.
- Itaconate's effects in organs beyond immune cells during sepsis are not well understood.
Purpose of the Study:
- To investigate the metabolic role of itaconate in the liver and systemically during sepsis.
- To elucidate the mechanisms by which itaconate influences lipid metabolism and fuel utilization.
Main Methods:
- Utilized Acod1 knockout mice lacking itaconate synthesis.
- Induced polymicrobial sepsis and endotoxin stimulation.
- Performed proteomics, chemoproteomics, and metabolic cage studies.
Main Results:
- Acod1 KO mice exhibited increased hepatic steatosis during sepsis.
- Itaconate treatment enhanced fatty acid oxidation enzyme expression and stabilized CPT1a via hypoubiquitination.
- Itaconate deficiency led to hypothermia and increased reliance on carbohydrates for fuel.
Conclusions:
- Itaconate is crucial for modulating hepatic lipid metabolism and fatty acid oxidation during sepsis.
- Itaconate deficiency impacts systemic energy homeostasis and thermoregulation.
- This study reveals a novel metabolic function of itaconate in sepsis.
More Related Videos
Related Concept Videos
01:24Drugs for Treatment of Crohn's Disease in IBD Using Biologic Agents: Anti-TNF
137
Tumor Necrosis Factor (TNF), a proinflammatory cytokine, contributes significantly to the inflammation seen in Crohn's disease. It exists as soluble TNF and membrane-bound TNF, with actions mediated through TNF receptors (TNFR). TNFR activation leads to the release of proinflammatory cytokines, T-cell activation, collagen production, and leukocyte migration, all contributing to inflammation in Crohn's disease. Anti-TNF monoclonal antibodies, namely infliximab (Remicade), adalimumab...
137
01:19Allosteric Proteins-ATCase
5.7K
Binding sites linkages can regulate a protein's function. For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
5.7K
01:21Drugs for Treatment of Constipation-Predominant IBS
169
Pharmacological therapies for IBS-C are designed to alleviate abdominal discomfort and enhance bowel function. In patients with IBS-C, fiber supplements may help soften stools and decrease straining, but may also lead to increased gas production and bloating. Osmotic laxatives like milk of magnesia are frequently used to soften stools and increase stool frequency in IBS-C patients. In addition, two drugs approved for use in severe IBS-C adult cases are linaclotide (Linzess) and lubiprostone...
169
01:29Drugs for Treatment of Crohn's Disease in IBD Using Immunomodulatory Agents
166
Crohn's disease is an inflammatory bowel disorder marked by chronic inflammation of the GI tract. Various treatment strategies for Crohn's disease are employed, such as immunomodulatory agents, glucocorticoids, and biologics or anti-TNF therapy. Azathioprine (Imuran), a commonly used immunomodulatory drug for Crohn's disease, is converted in the body to mercaptopurine, which inhibits purine biosynthesis and cell proliferation. Both are utilized in severe cases of Inflammatory Bowel...
166
01:29Drugs for Treatment of Ulcerative Colitis in IBD
141
Ulcerative colitis is a chronic inflammatory condition primarily affecting the colon and rectum. The primary drugs used in the treatment of ulcerative colitis are aminosalicylates. They exhibit anti-inflammatory and immunosuppressive properties. They modulate inflammatory mediators and inhibit the activity of nuclear factor κB (NF-κB). Aminosalicylates also reduce inflammation by inhibiting prostaglandin and leukotriene production and decreasing neutrophil chemotaxis and superoxide...
141
01:29Inflammatory Bowel Disease IV: Pharmacological Management
127
Upon diagnosis, managing Inflammatory Bowel Disease (IBD) involves addressing several crucial aspects. The primary goals include resting the bowel, correcting malnutrition, and providing symptomatic relief. Resting the bowel may consist of medications to reduce inflammation and promote healing. Correcting malnutrition is essential, often requiring dietary adjustments and nutritional supplements. Symptomatic relief aims to ease pain, diarrhea, and other discomforts in IBD.
Pharmacologic...
Pharmacologic...
127