REGULATION OF FATTY ACID SYNTHESIS | Annual …
Their general formula is R-CO-NHOH.
These compounds are receiving a lot of attention due to their biological activity as inhibitors of cyclooxygenase and 5-lipoxygenase with potent topical antiinflammatory activity (), metal chelators, agent for removing impurities from mineral ores, efficient surfactants in the detergent industry ().
Contrary to some short chain hydroxamic acids, fatty hydroxamic acids are not commercially available and are synthesized chemically () or by lipase-catalyzed reaction ().
Azamacrolides are alkaloids found in defensive droplets from glandular hairs of the pupa of the Mexican bean beetle, ().
Regulation of Cholesterol and Fatty Acid Synthesis
As we have outlined in this article, the discovery of the SREBP pathway nearly 20 years ago has led to major advances in the understanding of molecular mechanisms that govern the synthesis and uptake of cholesterol and fatty acids. Despite these advances at both the cellular and whole-animal level, key questions remain. For example, what is the molecular basis for the interactions of cholesterol and oxysterols with the membrane domain of Scap and Insigs, respectively? What amino acid residues in these proteins mediate sterol binding? How do interactions with sterols trigger formation of the Scap-Insig complex? Answers to these questions can only be provided by detailed structural analysis of Scap and Insigs by X-ray crystallography. This is an especially challenging task considering the insolubility of sterols in aqueous solution and the requirement of detergents to solubilize the hydrophobic Scap and Insig proteins.
In general, oxylipins are bioactive metabolites involved in regulating developmental processes and in environmental and pathological responses.
Very-long-chain fatty acids (C28C34) containing a hydroxy group at the n-18 position have been identified in the microalgae from the genus
Synthesis of saturated fatty acids via Fatty Acid Synthase ..
Complete lethality was observed following germline deletion of the SREBP-2 gene in mice with mortality occurring at embryonic days 7–8 (). Homozygous disruption of the SREBP-1 gene, which eliminated both the SREBP-1a and SREBP-1c transcripts, led to partial lethality; 15%–45% of the mice survive past embryonic day 11. The surviving SREBP-1 knockout mice appeared normal at birth and throughout adulthood. Their livers showed reduced synthesis of fatty acids, owing to reduced expression of fatty acid biosynthetic genes. To compensate for the loss of SREBP-1, livers of the knockout mice manifest elevated levels of SREBP-2 mRNA and protein leading to increased transcription of cholesterol biosynthetic genes and increased cholesterol synthesis. In contrast to SREBP-1 and SREBP-2 knockout mice, selective disruption of SREBP-1c did not cause embryonic lethality; the animals showed reduced expression of fatty acid biosynthetic genes and reduced fatty acid synthesis (). In addition, the compensatory increase in SREBP-2 activity and cholesterol synthesis was also observed in SREBP-1c knockouts.
Regulation of fatty acid synthesis ..
The final animal model for SREBP activation was created through germline disruption of the Insig-2 gene and liver-specific disruption of the Insig-1 gene through Cre-mediated recombination (). On a normal chow diet, these mice (designated L-Insig-1−/−; Insig-2−/−) overaccumulate cholesterol and triglycerides in the liver, but levels of nSREBPs and their target genes were not reduced. Cholesterol feeding failed to inhibit SREBP processing, reduce expression of lipogenic genes, and block lipid synthesis in Insig-1/-2 double knockout mice. Moreover, the level of HMG CoA reductase protein, the rate-limiting enzyme in cholesterol synthesis, was disproportionately elevated compared to its mRNA in the livers. This observation is consistent with studies in cultured cells showing that Insigs not only mediate sterol-mediated ER retention of Scap, but they also mediate sterol-accelerated degradation of HMG CoA reductase (; ; ). Like Scap, HMG CoA reductase contains a sterol-sensing domain within its NH2-terminal membrane attachment region that precedes a large cytosolic domain; the cytosolic domain of HMG CoA reductase exerts all enzymatic activity (; ). Accumulation of sterols causes Insigs to bind to the membrane domain of HMG CoA reductase, initiating a series of reactions that lead to the polyubiquitination of the enzyme and its subsequent degradation by proteasomes. Together, these observations highlight the importance of Insigs in the regulation of lipid synthesis in the liver.
Regulation of Fatty Acid Synthesis - ResearchGate
Transgenic mice that express a mutant version of Scap in the liver containing an asparagine substitution for aspartic acid-443 (D443N) in the sterol-sensing domain represents another animal model in which the SREBP pathway is activated (). In cultured cells, the D443N mutation in Scap abolishes its binding to Insigs, which renders the protein refractory to sterol-mediated ER retention (; ). Thus, D443N Scap continues to facilitate transport-dependent activation of SREBPs in the presence of sterols and cells expressing the mutant protein overproduce cholesterol. Similarly, transgenic mice expressing Scap D443N in the liver produce elevated levels of nSREBPs as compared to wild type controls (). Correspondingly, expression of genes required for synthesis and uptake of cholesterol and fatty acids were increased and the livers accumulated large amounts of cholesterol and triglycerides. When subjected to a diet enriched in cholesterol, processing of SREBPs was markedly resistant to suppression, demonstrating an essential role for Scap as a sterol sensor in the liver ().