Abstract
In animal cells, the primary repositories of esterified fatty acids and alcohols (neutral lipids) are lipid droplets that form on the lumenal and/or cytoplasmic side of the endoplasmic reticulum (ER) membrane. A monolayer of amphipathic lipids, intermeshed with key proteins, serves to solubilize neutral lipids as they are synthesized and desorbed. In specialized cells, mobilization of the lipid cargo for delivery to other tissues occurs by secretion of lipoproteins into the plasma compartment. Serum lipoprotein assembly requires an obligate structural protein anchor (apolipoprotein B) and a dedicated chaperone, microsomal triglyceride transfer protein. By contrast, lipid droplets that form on the cytoplasmic face of the ER lack an obligate protein scaffold or any required chaperone/lipid transfer protein. Mobilization of neutral lipids from the cytosol requires regulated hydrolysis followed by transfer of the products to different organelles or export from cells. Several proteins play a key role in controlling droplet number, stability, and catabolism; however, it is our premise that their formation initiates spontaneously, solely as a consequence of neutral lipid synthesis. This default pathway directs droplets into the cytoplasm where they accumulate in many lipid disorders.
Highlights
In animal cells, the primary repositories of esterified fatty acids and alcohols are lipid droplets that form on the lumenal and/or cytoplasmic side of the endoplasmic reticulum (ER) membrane
We contend that simple thermodynamic principles predict that synthesis of neutral lipids, in the absence of intervention by proteins other than the biosynthetic acyltransferases, is sufficient to form an oil droplet (Fig. 7)
The most accepted initial trajectory for this insoluble lipid resource involves the formation of a “lens” of neutral lipid that acquires a phospholipid coat from the ER bilayer
Summary
Numerous enzymatic reactions located in several organelles direct the incorporation of acetate into neutral lipids; the terminal and committed step of conjugation of alcohols (e.g., diacylglycerol and sterols) with free fatty acids is primarily performed at the ER membrane. PDAT gene family members (Fig. 3B) are typified by the mammalian lecithin cholesterol acyltransferase (LCAT) enzyme, the predominant product of which is cholesteryl ester This reaction resides primarily in the plasma compartment and uses lipoprotein-associated sterols as substrates. MTP activity creates a concentration gradient that is essential for transferring neutral lipids into the lumen of the ER that is further stabilized by apoB for secretion The directionality of this process is reversible, in that liver-specific genetic ablation or chemical inhibition of MTP impedes VLDL formation and enhances accumulation of CLDs in the cytoplasm, resulting in hepatic steatosis [24]. None of these models are mutually exclusive; certainly no “smoking gun” to any of them is currently available
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