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

Abstract

Here, we report that LCAT-deficient mice (DKO and Lcat) are protected against high fat high sucrose (HFHS) diet-induced obesity without hypophagia in a gender-specific manner compared with their respective (SKO and WT) controls. The metabolic phenotypes are more pronounced in the females. Changes in endoplasmic reticulum stress were examined as a possible mechanism for the metabolic protection. The female DKO mice developed attenuated HFHS-induced endoplasmic reticulum stress as evidenced by a lack of increase in mRNA levels of the hepatic unfolded protein response (UPR) markers Grp78 and CHOP compared with SKO controls. The DKO female mice were also protected against dietinduced insulin resistance. In white adipose tissue of chow-fed DKO mice, we also observed a reduction in UPR, gene markers for adipogenesis, and markers for activation of Wnt signaling. In skeletal muscles of female DKO mice, we observed an unexpected increase in UCP1 in association with increase in phospho-AMPK␣, PGC1␣, and UCP3 expressions. This increase in UCP1 was associated with ectopic islands of brown adipocytes between skeletal muscle fibers. Our findings suggest that LCAT deficiency confers gender-specific protection against diet-induced obesity and insulin resistance at least in part through regulation in UPR, white adipose tissue adipogenesis, and brown adipocyte partitioning. LCAT2 is an important enzyme in the regulation of high density lipoprotein (HDL) metabolism and in modulating plasma HDL cholesterol levels. LCAT mediates the esterification of cholesterol primarily in HDL but also to a limited extent in LDLs. Familial complete LCAT deficiency in humans is characterized by extremely low levels of plasma HDL cholesterol. In addition, commonly observed lipid phenotypes include elevated plasma level of phospholipid, free cholesterol to cholesterol ester ratio, and modest hypertriglyceridemia, the latter characterized by combined hepatic triglyceride overproduction and partially reduced lipoprotein lipase activity (1, 2). Recent human studies in a large cohort of subjects with familial LCAT deficiencies suggest that low LCAT may protect against atherosclerosis (3). However, studies in subjects with low LCAT in the general population yielded conflicting results (4). 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

Gender-Dependent Associations of Metabolite Profiles and Body Fat Distribution in a Healthy Population with Central Obesity: Towards Metabolomics Diagnostics

“…A positive relation between LCAT and obesity has been described (Sutherland et al. 1979) and LCAT-null mice have been shown to be protected from dietinduced obesity (Li et al, 2011). Therefore, the relative high level of LCAT in obese subjects may be responsible for clearance of specific PC species.…”

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

“…Furthermore, recently it was reported that LCAT-defi cient mice, especially females, are protected against high-fat high-sucrose (HFHS) dietinduced obesity ( 76 ). These protective metabolic phenotypes are associated with protection against diet-induced hepatic and adipocyte endoplasmic reticulum (ER) stress, but the mechanistic link with the enzymatic action of LCAT needs further investigation.…”

The Involvement of Cholesterol in Sepsis and Tolerance to Lipopolysaccharide Highlighted by the Transcriptome Analysis of Zebrafish (Danio rerio)

“…Phosphatidylcholine-sterol acyltransferase or lecithincholesterol acyltransferase (LCAT) was up-modulated at 4 dpf, and it is a key enzyme in the intravascular metabolism of HDL cholesterol. 44 Importantly, cholesterol 25-hydroxylase (CH25H) was significantly up-modulated at 6 dpf, and it is thought to play a role in the inflammatory response because its expression is induced rapidly, selectively, and robustly by the TLR ligands poly I:C and LPS. [45][46][47][48] Transcriptome after mild (SLD) LPS treatment…”