Genetic deficiency of apolipoprotein D in the mouse is associated with nonfasting hypertriglyceridemia and hyperinsulinemia

Abstract

Apolipoprotein D (ApoD) is an atypical apolipoprotein with an incompletely understood function in the regulation of triglyceride and glucose metabolism. We have demonstrated that elevated ApoD production in mice results in improved postprandial triglyceride clearance. This work studies the role of ApoD deficiency in the regulation of triglyceride and glucose metabolism and its dependence on aging. We used ApoD knockout (ApoD-KO) mice of 3 and 21 months of age. Body weight and food intake were measured. Hepatic histology, triglyceride content, lipoprotein lipase levels, and plasma metabolites were studied. Phenotypic characterization of glucose metabolism was performed using glucose tolerance test. β-Cell mass, islet volume, and islet number were analyzed by histomorphometry. Apolipoprotein D deficiency results in nonfasting hypertriglyceridemia in young (P = .01) and aged mice (P = .002). In young ApoD-KO mice, hypertriglyceridemia was associated with 30% to 50% increased food intake in nonfasting and fasting conditions, respectively, without changes in body weight. In addition, lipoprotein lipase levels were reduced by 35% in adipose tissue (P = .006). In aged ApoD-KO mice, hypertriglyceridemia was not associated with changes in food intake or body weight, whereas hepatic triglyceride levels were reduced by 35% (P = .02). Furthermore, nonfasting plasma insulin levels were elevated by 2-fold in young (P = .016) and aged (P = .004) ApoD-KO mice, without changes in blood glucose levels, glucose tolerance, β-cell mass, or islet number. These findings underscore the importance of ApoD in the regulation of plasma insulin levels and triglyceride metabolism, suggesting that ApoD plays an important role in the pathogenesis of dyslipidemia. © 2011 Elsevier Inc. All rights reserved. M E T A B O L I S M C L I N I C A L A N D E X P E R I M E N T A L6 0 ( 2 0 1 1 ) 1 7 6 7 -1 7 7 4Author contributions: The experiments were performed at the laboratories of DS, MDG, GP, and IC. GP, DS, and IC participated in the conception, design, analysis, and interpretation of the data. GP wrote the manuscript; and DS, IC, and MDG revised it critically for important intellectual content. MJP and MDG participated in the collection, analysis, and interpretation of the data. All authors approved the final version of the manuscript.

Aging without Apolipoprotein D: Molecular and cellular modifications in the hippocampus and cortex

“…In this context, we first find that mouse lifespan is not altered by ApoD deletion, in spite of the known metabolic (Do Carmo et al, 2009;Jimenez-Palomares et al, 2011;Perdomo et al, 2010) and cardiovascular (Leung et al, 2004;Tsukamoto et al, 2013) ApoD-dependent alterations, as well as the longevity regulatory functions described for invertebrate ApoD homologues (Hull-Thompson et al, 2009;Ruiz et al, 2011;Sanchez et al, 2006). However, within this normal lifespan, ApoD-KO mice clearly show signs of neurodegeneration, cognitive impairment and behavioral alterations at an age when mortality risks are still low.…”

Differential expression of apolipoprotein D in male reproductive system of rats by high‐fat diet

“…It is a constituent of HDL in plasma and appears less abundant in LDL and very low‐density lipoprotein (VLDL). In addition, Apod ‐deficient mice have a reduction in lipoprotein lipase activity and induction of the hypertriglyceridemia (Jimenez‐Palomares et al ., ). Moreover, three missense mutations within APOD gene increase levels of triglycerides and decrease HDL in plasma (Desai et al ., ).…”

Osteopontin-a alters glucose homeostasis in anchorage-independent breast cancer cells

“…STAT3, IGFBP5, and apolipoprotein D, which are targets of osteopontin-a signaling, have been described to contribute to glucose homeostasis. Previously, these observations had been made in cell types and organs other than the breast [21-23] and had not been linked to osteopontin. Osteopontin signaling has been studied extensively.…”