LCAT-null mice develop improved hepatic insulin sensitivity through altered regulation of transcription factors and suppressors of cytokine signaling

Abstract

We previously reported that LCAT-deficient mice develop not only low HDL-cholesterol but also hypertriglyceridemia, hepatic triglyceride (TG) overproduction, and, unexpectedly, improved hepatic insulin sensitivity and reduced hepatic TG content. Here, we examined the mechanistic links underlying this apparent paradox. The LDL receptor-deficient (Ldlr)(-/-)xLcat(-/-) mouse model and age- and sex-matched Ldlr(-/-)xLcat(+/+) littermates, both in C57Bl/6 background, were employed. Studies of hepatic insulin signal transduction showed an upregulation of hepatic Irs2 mRNA level (5.3-fold, P = 0.02), IRS-2 protein mass level (1.5-fold, P = 0.009) and pIRS-2 (1.8-fold. P = 0.02) in the Ldlr(-/-)xLcat(-/-) mice. There was a 1.2-fold increase in pAkt (P = 0.03) with a nonsignificant change in total Akt. We observed a significant shift in its downstream transcription factor FoxO-1 to the cytosolic compartment (2.3-fold increase in cytosolic/nuclear ratio, P = 0.04). We also observed a significant 3.1-fold increase in nuclear abundance of FoxA-2 mass (P = 0.017) and a 1.5-fold upregulation of its coactivator PGC-1beta (P = 0.002), the coordinated actions of which promotes hepatic TG production and beta-oxidation. Increased hepatic insulin signaling in the Ldlr(-/-)xLcat(-/-) mice was associated with an upregulation of the Tcfe3 gene (1.7-fold, P = 0.024), a selective downregulation of the Socs-1 gene by 60% (P = 0.01), and no change in PTP-1B protein mass. These data suggest that LCAT deficiency induces complex alterations in hepatic signal transduction cascades, which explain, at least in part, the observed enhanced insulin signaling in association with hepatic TG overproduction and reduced hepatic TG content.

Distinct metabolic and vascular effects of dietary triglycerides and cholesterol in atherosclerotic and diabetic mouse models

“…Cholesterol derivatives have important signaling properties in the liver through the liver X receptor receptor family and are known to improve glucose metabolism and may be involved in this unexpected improvement of insulin sensitivity (13). The suppression of the lecithin cholesterol acyltransferase gene in LDLr Ϫ/Ϫ animals led to increased circulating free cholesterol and improved hepatic insulin signaling (18). A lack of functional LDL receptors has previously been reported to protect peripheral tissues against ectopic accumulation of cholesterol and the lipotoxicity resulting from cholesterol accumulation (17).…”

Lecithin Cholesterol Acyltransferase Null Mice Are Protected from Diet-induced Obesity and Insulin Resistance in a Gender-specific Manner through Multiple Pathways

“…mRNA Quantitation of Hepatic, Adipose Tissues, and Skeletal Muscle Genes-RNA was extracted from the liver, white and brown adipose tissues, and skeletal muscle using TRIzol (Invitrogen) as described previously (5). For real time PCR analysis, RNA was reverse transcribed using QuantiTect reverse transcription kit following the manufacturer's protocol (Qiagen) and SYBR Green PCR master mix (Applied Biosystems, Foster City, CA) was used in quantitative PCR and was conducted in the ABI PRISM machine 7900HT sequence detection system operated with the respective SDS software (version 2.1).…”

“…Insulin Tolerance Test (ITT)-After a 6-h fast, the study mice were subjected to intraperitoneal ITT as previously described (5).…”

“…On the other hand, the potential role for LCAT in the modulation of glucose and energy homeostasis has received little attention. Our laboratory was the first to report that, in the LDL receptor knock-out mouse background and under chow-fed conditions, the genetic absence of LCAT (Ldlr Ϫ/Ϫ ϫLcat Ϫ/Ϫ mice) is associated with enhanced insulin sensitivity when compared with the Ldlr Ϫ/Ϫ ϫLcat ϩ/ϩ control mice (4,5). The impact of these novel phenotypes in response to obesogenic and diabetogenic stresses remains to be fully elucidated.…”

Lecithin:cholesterol acyltransferase: old friend or foe in atherosclerosis?

“…LCAT defi ciency in mice is associated with enhanced insulin sensitivity ( 74,75 ). Furthermore, recently it was reported that LCAT-defi cient mice, especially females, are protected against high-fat high-sucrose (HFHS) dietinduced obesity ( 76 ).…”