Sterol O-Acyltransferase Inhibition Ameliorates High-Fat Diet-Induced Renal Fibrosis and Tertiary Lymphoid Tissue Maturation after Ischemic Reperfusion Injury

Metabolic syndrome is associated with the development of chronic kidney disease (CKD). We previously demonstrated that aged kidneys are prone to developing tertiary lymphoid tissues (TLTs) and sustain inflammation after injury, leading to CKD progression; however, the relationship between renal TLT and metabolic syndrome is unknown. In this study, we demonstrated that a high-fat diet (HFD) promoted renal TLT formation and inflammation via sterol O-acyltransferase (SOAT) 1-dependent mechanism. Mice fed a HFD prior to ischemic reperfusion injury (IRI) exhibited pronounced renal TLT formation and sustained inflammation compared to the controls. Untargeted lipidomics revealed the increased levels of cholesteryl esters (CEs) in aged kidneys with TLT formation after IRI, and, consistently, the Soat1 gene expression increased. Treatment with avasimibe, a SOAT inhibitor, attenuated TLT maturation and renal inflammation in HFD-fed mice subjected to IRI. Our findings suggest the importance of SOAT1-dependent CE accumulation in the pathophysiology of CKDs associated with TLT.

 

Comments：

The study demonstrated that a high-fat diet (HFD) can promote the formation of tertiary lymphoid tissues (TLTs) and inflammation in the kidneys via a mechanism involving sterol O-acyltransferase (SOAT) 1. The researchers found that mice fed an HFD prior to ischemic reperfusion injury (IRI) exhibited more pronounced renal TLT formation and sustained inflammation compared to the control group. The increased formation of TLTs was associated with higher levels of cholesteryl esters (CEs) in the kidneys, which was found to be SOAT1-dependent. Treatment with avasimibe, a SOAT inhibitor, was found to attenuate TLT maturation and renal inflammation in HFD-fed mice subjected to IRI.

These findings suggest that SOAT1-dependent CE accumulation may play an important role in the development of chronic kidney disease (CKD) associated with TLT formation. The study highlights the potential of targeting SOAT1 as a therapeutic strategy for CKD prevention and treatment in individuals with metabolic syndrome.

 

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Cat.No.	Product Name	Information
S2187	Avasimibe	Avasimibe inhibits ACAT with IC50 of 3.3 μM, also inhibits human P450 isoenzymes CYP2C9, CYP1A2 and CYP2C19 with IC50 of 2.9 μM, 13.9 μM and 26.5 μM, respectively.

Related Targets

Acyltransferase P450 (e.g. CYP17)