TLR2-Deficiency Promotes Prenatal LPS Exposure-Induced Offspring Hyperlipidemia

Abstract

Toll-like receptor 2 (TLR2), which recognizes several lipopeptides and transduces inflammatory signaling, promotes the pathogenesis of diet-induced dyslipidemia and obesity. TLR2-deficient mice were shown to have improved insulin sensitivity and reduced diet-induced metabolic syndrome. Previous studies demonstrated that prenatal lipopolysaccharide (LPS) exposure causes dyslipidemia accompanied by increased body weight and insulin resistance in offspring. To determine whether TLRs are involved in this complex abnormal phenotype, we analyzed TLR2 and TLR4 expression levels in adipose tissues from offspring with prenatal LPS-exposure (offspring-pLPS) and compared these levels to those of control offspring with prenatal saline-exposure (offspring-pSaline). TLR2 expression was specifically upregulated in the adipose tissue of offspring-pLPS mice. However, unexpectedly, TLR2-deficient offspring-pLPS mice not only presented with an abnormal phenotype comparable to that of wild-type offspring-pLPS mice but also exhibited significantly more severe hyperlipidemia. Our further analyses revealed a dramatic upregulation of TLR4 expression and overactivation of the TLR4/Myd88 signaling pathway in TLR2-deficient offspring-pLPS adipose tissue. Our finding suggests a compensatory genetic interaction between TLR2 and TLR4 in the context of prenatal inflammatory stimulation, and this interaction likely contributes to the prenatal inflammation-induced hyperlipidemia and lipid overload-induced obesity, thus providing a potential mechanism for the fetal origin of adult metabolic diseases.

Palmitate Stimulates Expression of the von Willebrand Factor and Modulates Toll-like Receptors Level and Activity in Human Umbilical Vein Endothelial Cells (HUVECs)

“…On the other hand, the silencing of TLR2 resulted in a small and transient increase in TLR4 protein level. These observations are in line with previously published data, indicating functional and structural crosstalk between these receptors [69,70].…”

“…C29 induced the upregulation of TLR4-encoding gene and protein levels, which may be at least partially responsible for the observed effect. A similar phenomenon was reported in mice deficient in TLR2 or TLR4 [ 69 , 70 ]. In contrast, Jang et al [ 35 ] found that the silencing of the TLR2 gene resulted in a substantial reduction in the TNF-α level.…”

Targets of statins intervention in LDL-C metabolism: Gut microbiota

“…However, we are yet to determine whether LPS damage to the gut affects the FXR and PXR pathways in enterocytes, thereby affecting the regulation of cholesterol by the gut microbiota. We observed that LPS translocation causes abnormal cholesterol metabolism and elevated serum LDL-C levels via TLR4-Myd88 in hepatocytes ( 106 – 109 ), which can be prevented by statins. Moreover, TLR4-Myd88 can activate both ERK and JNK signaling pathways in mice hepatocytes, thereby inhibiting CYP7A1 expression ( 132 ).…”

“…Cao et al (2019) suggested more pronounce serum LDL-C changes in TLR2 knockout offspring mice and indicated that this may be due to a compensatory increase in TLR4 caused by TLR2 deficiency, manifested by an increased expression of TLR4 and Myd88 overactivity. Thus, the presence of LPS led to elevated serum LDL-C levels by activating TLR4 ( 106 ). Studies have discovered that the TLR4-Myd88 signaling pathway is related to lipid metabolism, as shown by the fact that the lipid-lowering effects of multiple lipid-lowering drugs are eliminated in Myd88 knockout mice ( 107 ).…”

Potential Mechanisms of Gut-Derived Extracellular Vesicle Participation in Glucose and Lipid Homeostasis

“…However, the interaction between TLR2 and LPS/TLR4 signaling pathways causes an opposing observation. Cao et al found that TLR2-deficient offspring of mice with prenatal LPS exposure had significantly more severe hyperlipidemia compared with WT offspring, with compensative upregulation of the TLR4/Myd88 signaling pathway in the adipose tissue [ 91 ].…”