Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0015695 (fatty liver)
 13,941 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Classically activated macrophages (M1) secrete proinflammatory cytokine and are predominant in obese adipose tissue. M2 macrophages, prevalent in lean adipose tissue, are induced by IL-13 and IL-4, mainly secreted by Th2 lymphocytes, and produce the anti-inflammatory cytokine IL-10. ITCH is a ubiquitously expressed E3 ubiquitin ligase involved in T-cell differentiation and in a wide range of inflammatory pathways. ITCH downregulation in lymphocytes causes aberrant Th2 differentiation. To investigate the role of Th2/M2 polarization in obesity-related inflammation and insulin resistance, we compared wild-type and Itch(-/-) mice in a context of diet-induced obesity (high-fat diet [HFD]). When subjected to HFD, Itch(-/-) mice did not show an increase in body weight or insulin resistance; calorimetric analysis suggested an accelerated metabolism. The molecular analysis of metabolically active tissue revealed increased levels of M2 markers and genes involved in fatty acid oxidation. Histological examination of livers from Itch(-/-) mice suggested that ITCH deficiency protects mice from obesity-related nonalcoholic fatty liver disease. We also found a negative correlation between ITCH and M2 marker expression in human adipose tissues. Taken together, our data indicate that ITCH E3 ubiquitin ligase deficiency protects from the metabolic disorder caused by obesity.
...
PMID:ITCH deficiency protects from diet-induced obesity. 2417 Jun 94

Atherosclerosis is a chronic inflammatory disease characterized by the infiltration of pro-inflammatory macrophages into a lipid-laden plaque. ITCH is an E3 ubiquitin ligase that has been shown to polarize macrophages to an anti-inflammatory phenotype. We therefore investigated the effect of ITCH deficiency on the development of atherosclerosis. ApoE-/-ITCH-/- mice fed a western diet for 12 weeks showed increased circulating M2 macrophages together with a reduction in plaque formation. Bone marrow transplantation recreated the haemopoietic phenotype of increased circulating M2 macrophages but failed to affect plaque development. Intriguingly, the loss of ITCH lead to a reduction in circulating cholesterol levels through interference with nuclear SREBP2 clearance. This resulted in increased LDL reuptake through upregulation of LDL receptor expression. Furthermore, ApoE-/-ITCH-/- mice exhibit reduced hepatic steatosis, increased mitochondrial oxidative capacity and an increased reliance on fatty acids as energy source. We found that ITCH ubiquitinates SIRT6, leading to its breakdown, and thus promoting hepatic lipid infiltration through reduced fatty acid oxidation. The E3 Ubiquitin Ligase ITCH modulates lipid metabolism impacting on atherosclerosis progression independently from effects on myeloid cells polarization through control of SIRT6 and SREBP2 ubiquitination. Thus, modulation of ITCH may provide a target for the treatment of hypercholesterolemia and hyperlipidemia.
...
PMID:ITCH modulates SIRT6 and SREBP2 to influence lipid metabolism and atherosclerosis in ApoE null mice. 2577 60