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distant future.

**Author details** 

**7. References** 

steatosis and decreased in liver of patients with severe insulin resistance, suggesting that ChREBP, alone or in combination with LXR, drives SCD1 expression and steatosis independent of insulin resistance. This is in line with recent human studies showing no relationship between hepatic TG accumulation and insulin resistance (Cohen et al., 2011; Hooper et al., 2011). Thus, hepatic steatosis can either be the result or cause of hepatic insulin resistance. The mechanisms of hepatic insulin resistance is still not clear (Farese, Jr. et al., 2012), but may involve specific lipids, nutrition-induced metabolites and PTMs including O-GlcNAc. Hepatic TG synthesis may be a protective mechanism to limit accumulation of toxic free fatty acids, liver damage and fibrosis (Choi & Diehl, 2008) where

As LXR is shown also to act anti-inflammatory in liver (Wouters et al., 2008; Venteclef et al., 2010), LXR activation may be an important compensative mechanism in response to excess nutrients to limit liver damage, inflammation and fibrosis. SUMOylation is an important ligand-activated transrepressional PTM of LXR on inflammatory genes (Venteclef et al., 2011) and future studies in our laboratory aim to elucidate a putative cross-talk between OGT and E3 ligases (SUMO conjugating enzymes) in liver in response to excess nutrients, especially high sugar levels (glucose and fructose). The relative roles of LXR, SREBP1c and ChREBP in driving lipogenesis is clearly dependent on both insulin and glucose signaling and cross-talk between these pathways. Both phosphorylation and GlcNAcylation appear instrumental in hepatic lipogenesis and future focus in our laboratory will be to elucidate a possible cross-talk between these PTMs, endogenous LXR ligands and interacting CAs in response to various feeding conditions (high glucose, fructose and/or fatty acids, cholesterol) and the impact on downstream ChREBP, SREBP1c and lipogenic enzyme expression and activity. ChIP and reChIP analysis in combination with loss of function studies have become powerful tools to analyze activation of specific genes by specific transcription factors in response to extracellular stimuli. By these methods, we anticipate that the signaling mechanisms and relative roles of LXR, ChREBP, SREBP1c and cooperating transcription factors in driving hepatic *de novo* lipogenesis will be revealed in the not too

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**Chapter 5** 

© 2013 Dimitrova-Shumkovska et al., licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

reduced apoE3 levels relative to apoE4 levels (Buttini et al., 1999; Sheng et al., 1998).

and reproduction in any medium, provided the original work is properly cited.

properly cited.

**The 18 kDa Translocator Protein and** 

Additional information is available at the end of the chapter

**1.1. Apolipoprotein E, inflammation and atherosclerosis** 

http://dx.doi.org/10.5772/54974

**1. Introduction** 

**Atherosclerosis in Mice Lacking Apolipoprotein E** 

Jasmina Dimitrova-Shumkovska, Leo Veenman, Inbar Roim and Moshe Gavish

The inflammatory disease atherosclerosis is characterized by plaque formation in the cardiovascular system, which together with thrombosis can lead to obstruction of blood vessels, potentially leading to ischemia, stroke, and heart failure (Libby et al., 2009; Chen et al., 2010; Drake et al., 2011). Atherosclerosis is triggered and sustained by inflammation related cytokines, chemokines, adhesion molecules and by the cellular components of the immune system (Ross, 1999; Epstein et al., 2004). Cholesterol, most of it transported as a low density lipoprotein (LDL) particle in the bloodstream, supports foam cell formation in atherosclerotic plaques. In parallel, cholesterol plays an important role in steroidogenesis and bile production (Lacapere and Papadopoulos, 2003), which have been correlated with mitochondrial 18 kDa Translocator Protein (TSPO) and apolipoprotein E (apoE) expression (Fujimura et al., 2008; Gaemperli et al., 2011). Lipoproteins are lipid transport vehicles that ensure the solubility of lipids within aqueous biological environments. Apolipoproteins stabilize the surface of lipoproteins, serve as cofactors for enzymatic reactions, and present themselves as ligands for lipoprotein receptors. The soluble apolipoprotein gene family, which includes apoE, encodes proteins with amphipathic structures that allow them to exist at the water-lipid interface (Chan, 1989). ApoE is a polymorphic 229-aa, 34-kDa protein, which is present in the cell nucleus and cytosolic compartments (Mahley & Huang, 1999). The human gene, located on chromosome 19, encodes three alleles: apoE2 (frequency in the human population, 5–10%), apoE3 (60–70%), and apoE4 (15–20%). The isoforms differ only at residues 112 and 158 (Cedazo-Minguez & Cowburn, 2001). However, there is only one isoform of apoE in mouse and it behaves like human apoE3 (Strittmatter & Bova Hill, 2002). It is suggested that apoE deficiency in mice mimics the human apoE4 status, which implies

