Lipotoxicity involves the excess delivery of fatty acids (FA) to sites other than adipose tissue. In vivo, fatty acids (FA) can arrive at the liver bound to albumin or as components of TG (TG)-enriched remnant lipoproteins (chylomicron and VLDL). In the latter instances, FA can be liberated from remnants by the action of hepatic lipase bound to capillaries in the hepatic vascular bed or released from lysosomes after receptor-mediated internalization of remnant lipoproteins. In addition to exogenously derived FA, increased availability of FA may result form their synthesis in the liver from acetylCoA via lipogenesis. The latter pathway has been linked recently to insulin resistance and hyperinsulinemia. The liver is unique in that it is able to """"""""unload"""""""" excess FA in bulk form by assembling and secreting apoB-lipoproteins. There are few data, however, concerning the effects of FA from each of the sources described above on the two-step process of apoB-lipoprotein assembly: the first step involves the targeting of nascent apoB across the ER membrane and assembly of a lipid-poor primordial lipoprotein, while the second step involves the bulk addition of core lipid to the primordial particle and the formation of the mature TG-rich apoB-lipoprotein. Importantly, it is not known if each of the pathways involved in providing increased FA within the hepatocyte impacts equally on FA synthesis and oxidation, genes involved in TG synthesis, or genes involved in the assembly and secretion of apoB-lipoproteins. The link between insulin resistance/hyperinsulinemia and increased VLDL secretion is also incompletely defined. In particular, the relative importance of hepatic lipogenesis versus plasma FA uptake by the liver in the increased apoB-lipoprotein secretion observed in insulin resistant animal models and humans has not been studied. The experiments proposed in this project are directed at unanswered questions related to FA regulation of apoB-lipoprotein assembly and secretion, including: (1) the effects of plasma albumin-delivered FA on each of the steps in apoB-lipoprotein assembly and the expression of genes involved in maintaining hepatic lipid homeostasis; (2) the effects TG-rich remnant-like particle-delivered FA on apoB-lipoprotein assembly and gene expression; and (3) the relative importance of insulin resistance/hyperinsulinemia versus increased plasma FA availability in the reaulation of apoB-lipoprotein assemblv and secretion.
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