Protection against Fatty Liver but Normal Adipogenesis in Mice Lacking Adipose Differentiation-Related Protein

Abstract

Adipose differentiation-related protein (ADFP; also known as ADRP or adipophilin), is a lipid droplet (LD) protein found in most cells and tissues. ADFP expression is strongly induced in cells with increased lipid load. We have inactivated the Adfp gene in mice to better understand its role in lipid accumulation. The Adfpdeficient mice have unaltered adipose differentiation or lipolysis in vitro or in vivo. Importantly, they display a 60% reduction in hepatic triglyceride (TG) and are resistant to diet-induced fatty liver. To determine the mechanism for the reduced hepatic TG content, we measured hepatic lipogenesis, very-low-density lipoprotein (VLDL) secretion, and lipid uptake and utilization, all of which parameters were shown to be similar between mutant and wild-type mice. The finding of similar VLDL output in the presence of a reduction in total TG in the Adfp-deficient liver is explained by the retention of TG in the microsomes where VLDL is assembled. Given that lipid droplets are thought to form from the outer leaflet of the microsomal membrane, the reduction of TG in the cytosol with concomitant accumulation of TG in the microsome of Adfp ؊/؊ cells suggests that ADFP may facilitate the formation of new LDs. In the absence of ADFP, impairment of LD formation is associated with the accumulation of microsomal TG but a reduction in TG in other subcellular compartments.Adipose differentiation-related protein (ADFP) was first isolated by differential hybridization screening of 1246 cells during their differentiation to adipocytes (29). Its mRNA is induced 100 fold during the process. Using 3T3L1 cells, Brasaemle et al. (3) showed that Adfp gene expression is induced early, at day 1 of adipocyte differentiation, and that mRNA levels are maintained throughout differentiation. In contrast, ADFP protein levels, initially upregulated, gradually go down after day 4 (3), suggesting that these levels are subject to significant translational or posttranslational regulation. At the same time, upregulation of perilipin (PLIN), another lipid droplet (LD) protein, is observed at day 4 of differentiation; it has been postulated that perilipin and ADFP might compete for LD localization during the differentiation of 3T3L1 cells (3, 36). ADFP protein is localized to the surface of the LD, though it also has been detected in the LD core by freeze fracture electron microscopy (49, 50).ADFP shares sequence homology with other LD proteins including perilipin and Tip47, collectively known as PAT domain-containing proteins (36, 43), as well as with another LD protein, S3-12 (53). S3-12 shares a 11-amino-acid repeat motif with ADFP, in addition to another region of homology to both ADFP and Tip47 at its carboxyl terminus (6,24,36). With the exception of perilipin, which is expressed only in fat and steroidogenic tissues, the other LD proteins are detected in a variety of cells and tissues (22). Perilipin is phosphorylated by protein kinase A during lipolysis, resulting in an altered conformation to allow hormone-sensitive lipase ...

Perilipin-2 Deletion Impairs Hepatic Lipid Accumulation by Interfering with Sterol Regulatory Element-binding Protein (SREBP) Activation and Altering the Hepatic Lipidome

“…Although it was shown that whole-body knock-out of Plin2 by targeting exons 2/3 led to a reduction in hepatic TG even on a chow diet (49), changes in the neutral lipid profile were not observed in this model. This could possibly be due to incomplete knock-out of the PLIN2 protein (50) and/or differences in dietary sucrose.…”

aP2-Cre-mediated inactivation of acetyl-CoA carboxylase 1 causes growth retardation and reduced lipid accumulation in adipose tissues

“…Long femur and tibia bones were dissected free of surrounding tissues, and homogenized in PBS buffer containing 40 mM EDTA (pH 8.0). The lipid was extracted and analyzed (42). The compositions of each fatty acid are expressed as Mol%.…”

OXPAT/PAT-1 Is a PPAR-Induced Lipid Droplet Protein That Promotes Fatty Acid Utilization

“…Perilipin and adipophilin are stable only in the presence of neutral lipid and, otherwise, are targeted to proteosomes for degradation (16,17). Perilipin and adipophilin are necessary for accumulation of large TAG stores in adipose tissue (7,8) and liver (6), respectively, and likely are important for regulation of constitutive TAG stores. Also, evidence has amassed that perilipin regulates and orchestrates the hydrolysis of adipose TAG stores (2,4,5,7,8).…”