Export of Mitochondrial Acetoacetate for Cytosolic Lipogenesis: Relevance to Interactions of Microsomal Cholesterogenesis & Mitochondrial Ketogenesis

This article [MacDonald et al., 2007: (http://www.jbc.org/cgi/content/full/282/42/30596)(http://www.ncbi.nlm.nih.gov/pubmed/17724028?dopt=Abstract)] is interesting, and the authors found that both citrate and acetoacetate could serve as "carriers" or could serve to "transfer" acetyl-CoA from the mitochondria to the cytosol in pancreatic beta cells. Citrate has traditionally been viewed as the only or primary tricarboxylic acid (TCA) cycle intermediate that could be transported across the inner mitochondrial membrane and, fairly directly, serve as a precursor for cytosolic acetyl-CoA and hence for lipogenesis. The authors found that acetoacetate was converted into acetyl-CoA in the cytosol by either of two cytosolic enzymes. Succinate evidently couldn't be converted into succinyl-CoA in the cytosol, but this may not be true in cell types other than beta cells.

This is relevant to an understanding of the ways dietary cholesterol or the cellular cholesterol concentration in general, both in cells within and outside the liver, could exert feedback inhibition of microsomal (endoplasmic-reticulum, cytosolic) HMG-CoA reductase activity, thereby increasing the microsomal/cytosolic HMG-CoA pool, and, in theory, exert some kind of influence on the availability of intramitochondrial HMG-CoA for ketogenesis in the mitochondria [the first page of this pdf is inaccessible, but the rest of the article is fine: Ott and Lachance, 1981: (http://www.ajcn.org/cgi/reprint/34/10/2295)(http://www.ncbi.nlm.nih.gov/pubmed/6170219?dopt=Abstract)]. The cytosolic and mitochondrial HMG-CoA pools are not thought to be interchangeable, and so it's not easy to see an obvious or simple mechanism by which an increase in the overall cellular cholesterol concentration could enhance ketogenesis. Part of the reason for this is that cholesterol biosynthesis and transport within cells are compartmentalized [Ott and Lachance, 1981; Liscum et al., 1995: (http://www.jbc.org/cgi/content/full/270/26/15443)(http://www.ncbi.nlm.nih.gov/pubmed/7797533)]. But the authors of that article mention the relationships between succinate transport across the inner mitochondrial membrane, anaplerosis, and mevalonate biosynthesis. I'll try to read some more about that, but it doesn't look like there's all that much information on it. My point is that, as with glutamine and many other compounds, the compartmentation complicates or makes impossible any attempt to draw simple or easy conclusions about enzyme regulation in response to changes in dietary or intracellular or extracellular cholesterol concentrations. I think there is some mechanism, though, because cholesterol biosynthesis is energetically very demanding, compared to many other small-molecule intermediates or regulatory compounds or whatever one wants to describe cholesterol as being.