Deletion of murine Arv1 results in a lean phenotype with increased energy expenditure

Abstract

Background:ACAT-related enzyme 2 required for viability 1 (ARV1) is a putative lipid transporter of the endoplasmic reticulum that is conserved across eukaryotic species. The ARV1 protein contains a conserved N-terminal cytosolic zinc ribbon motif known as the ARV1 homology domain, followed by multiple transmembrane regions anchoring it in the ER. Deletion of ARV1 in yeast results in defective sterol trafficking, aberrant lipid synthesis, ER stress, membrane disorganization and hypersensitivity to fatty acids (FAs). We sought to investigate the role of Arv1 in mammalian lipid metabolism.Methods:Homologous recombination was used to disrupt the Arv1 gene in mice. Animals were examined for alterations in lipid and lipoprotein levels, body weight, body composition, glucose tolerance and energy expenditure.Results:Global loss of Arv1 significantly decreased total cholesterol and high-density lipoprotein cholesterol levels in the plasma. Arv1 knockout mice exhibited a dramatic lean phenotype, with major reductions in white adipose tissue (WAT) mass and body weight on a chow diet. This loss of WAT is accompanied by improved glucose tolerance, higher adiponectin levels, increased energy expenditure and greater rates of whole-body FA oxidation.Conclusions:This work identifies Arv1 as an important player in mammalian lipid metabolism and whole-body energy homeostasis.

Mice lacking have reduced signs of metabolic syndrome and non-alcoholic fatty liver disease

“…As was shown previously (23,24), our Arv1 -/ -animals had reduced survival rates and suffered from seizures, which occasionally resulted in animals being euthanized. In addition to impaired locomotor coordination, Arv1 -/-mice were more active than WT mice in an open field, suggesting a generalized neurological defect.…”

“…Here, we examined how Arv1 -/ -animals responded metabolically to being fed a HFD. We point out that the KO line described in our paper was generated using a different strain of ES cells and gene targeting strategy as compared to the Arv1 KO mice previously described (23,24), indicating the observed phenotypes are robust and indeed related to the inactivation of the Arv1 gene. Thus, the current study describes the contribution of Arv1 to the DIO model phenotypes.…”

“…Palmer et al, (24) found that NKO Arv1 -/ -animals suffered from seizures and epileptic encephalopathy. Lagor et al, (23) discovered that Arv1 -/ -animals displayed multiple beneficial metabolic changes, including lack of weight gain, improved glucose tolerance, elevated adiponectin secretion, increased energy expenditure, and a decrease in WAT (white adipose tissue). These studies strongly suggest that Arv1 plays a critical role in maintaining brain function and metabolic homeostasis.…”

“…It has been shown that Arv1 -/ -mice display a lean phenotype (23). To test if our Arv1 -/ -animals shared this phenotype, we fed them a HFD (high fat diet) and determined its effects on weight gain.…”

Adipocyte Tribbles1 Regulates Plasma Adiponectin and Plasma Lipids in Mice

“…For HFD experiments, mice were placed on 45% kcal HFD (Research Diets D12451) starting at 8-12 weeks of age. Plasma was collected retro-orbitally at 0, 4, 8, and 12 weeks of HFD, and glucose tolerance testing performed at 0, 6, and 12 weeks of HFD as previously described [42]. For fasting/refeeding experiments, mice were fasted overnight for 16 hr and then fed ad-libitum with chow diet for 3hr.…”