Abstract
Apolipoprotein B-100 (ApoB) is a major component of very-low-density lipoproteins, and is deposited in a region around lipid droplets (LDs) called the ;ApoB-crescent'. The ApoB-crescent is thought to be related to ApoB degradation because it drastically increases when proteasome or autophagy is inhibited. In the present study, we found that ApoB-crescents were significantly reduced when ApoB lipidation was suppressed by either the inhibition or knockdown of the microsomal triglyceride-transfer protein. By contrast, ApoB-crescents increased under conditions that are presumed to cause lipidated ApoB abnormalities in secretory compartments. By electron microscopic analyses, we identified the ApoB-crescent as a thin cholesterol-rich ER cistern fused to an LD, and - topologically - this structure is equivalent to a lipid-ester globule between the two leaflets of the ER membrane. ApoB localized in the thin cisternal lumen, and its binding to LDs was resistant to alkaline treatment. Overexpression of ADRP or TIP47 suppressed the increase in the number of ApoB-crescents, whereas knockdown of these proteins had the opposite effect. From these results, we inferred that the ApoB-crescent is formed by an LD that is arrested in the ER membrane by tight binding of lipidated ApoB to its luminal surface. We suggest that ApoB processing and LD formation are closely linked.
Highlights
Lipid droplets (LDs) are ubiquitous cytoplasmic structures that consist of a neutral lipid core surrounded by a unique phospholipid monolayer (Murphy and Vance, 1999; Tauchi-Sato et al, 2002)
We inferred that the Apolipoprotein B-100 (ApoB)-crescent is formed by an LD that is arrested in the ER membrane by tight binding of lipidated ApoB to its luminal surface
LDs in hepatocytes are physiologically important as a lipid source for the production of very-low-density lipoprotein (VLDL) (Gibbons et al, 2000), but the excessive accumulation of LDs in hepatocytes is a hallmark of steatosis – or fatty liver – which may lead to liver cirrhosis or carcinoma (Ginsberg, 2006)
Summary
Lipid droplets (LDs) are ubiquitous cytoplasmic structures that consist of a neutral lipid core surrounded by a unique phospholipid monolayer (Murphy and Vance, 1999; Tauchi-Sato et al, 2002). LDs in hepatocytes are physiologically important as a lipid source for the production of very-low-density lipoprotein (VLDL) (Gibbons et al, 2000), but the excessive accumulation of LDs in hepatocytes is a hallmark of steatosis – or fatty liver – which may lead to liver cirrhosis or carcinoma (Ginsberg, 2006). The lipidation process may be facilitated by the addition of fatty acids, and when this occurs ApoB and VLDL secretion increases. It is thought, that other mechanisms to degrade lipidated ApoB in secretory compartments must exist, these molecular mechanisms have not been defined as yet (Liao et al, 1998; Fisher et al, 2001; Olofsson and Boren, 2005)
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