Regulation of lipid metabolism - Insulin regulation of fatty acid methabolism

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Insulin regulation of fatty acid methabolism

Insulin is powerful regulator of lipogenesis and lipolysis in insulin- dependent tissue, such as skeletal muscle, adipose tissue and liver.

Insulin is the most important physiological inhibitor of lipolysis. Hormone-sensitive lipase (LIPS) is the rate-limiting enzyme of this process. Activation of lipolysis is mediated by an increment of intracellular cAMP concentrations and activation of protein kinase A (PKA). The two main targets for PKA-mediated phosphorylation in the adipocyte are LIPS and the perilipins. Phosphorylation of these proteins dramatically increases lipolysis. Insulin induces phosphorylation and activation of the phosphodiesterase type 3B (PDE3B), leading to a decrease in cAMP levels and concomitant decrease of PKA activity. The signaling pathway leading to activation of the PDE3B involves the insulin receptor, insulin receptor substrates (IRS-1, IRS-2), phosphatidyl inositol-3 kinase (PI3K), and protein kinase B (AKT) [1]; [2].

Fatty acids are synthesized de novo from acetyl-CoA and malonyl-CoA through a series of reactions mediated by acetyl-CoA carboxylase (ACACA) and fatty acid synthase (FASN). Sterol regulatory element binding protein (SREBP-1) is selectively involved in activation of genes involved in fatty acid metabolism and de novo lipogenesis. SREBP-1 plays key role in insulin action on these processes.

Transcription factor SREBP-1 is produced as membrane-bound precursors that require cleavage by a two-step proteolytic process. SREBP precursor and SCAP (SREBP cleavage-activating protein) form a complex on the rough endoplasmic reticulum (ER) membrane. SCAP is prerequisite for cleavage of SREBP-1 [3], [4], [5].

Insulin receptor following its activation inhibits insulin induced gene 2 (INSIG2), a protein of the endoplasmic reticulum that blocks the processing of SREBP-1 by binding to SCAP, thus preventing it from escorting SREBP-1 to the Golgi [6].

SREBP-1 is a key transcriptional activator for early events in the initiation of lipogenesis. Insulin-induced expression of the glucokinase (HXK4) gene is mediated through a mechanism requiring SREBP-1 [7].

Early step of lipogenesis (fatty acid synthesis) also regulated by transcription factor SP1, its activation by typical insulin-induced ERK1/2 signaling pathway lead to activation of few enzymes, such as ATP citrate lyase(ACLY), acetyl-CoA carboxylase (ACACA), fatty acid synthase (FASN) [8], [9], [10].

SREBP-1 is markedly increased rate of fatty acid synthesis, owing to the activation of biosynthetic genes, which include ACLY, ACACA, FASN and stearoyl-CoA desaturase (FADS2). Also enzymes required for the elongation of palmitic to stearic acid induced. Long chain fatty acyl elongases (ELOVL1 and ELOVL6) are induced by SREBP-1 [11].



References

  1. Holm C, Osterlund T, Laurell H, Contreras JA
    Molecular mechanisms regulating hormone-sensitive lipase and lipolysis. Annual review of nutrition 2000;20:365-93
  2. Osterlund T
    Structure-function relationships of hormone-sensitive lipase. European journal of biochemistry / FEBS 2001 Apr;268(7):1899-907
  3. Shimano H
    Sterol regulatory element-binding proteins (SREBPs): transcriptional regulators of lipid synthetic genes. Progress in lipid research 2001 Nov;40(6):439-52
  4. Horton JD, Goldstein JL, Brown MS
    SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. The Journal of clinical investigation 2002 May;109(9):1125-31
  5. Weber LW, Boll M, Stampfl A
    Maintaining cholesterol homeostasis: sterol regulatory element-binding proteins. World journal of gastroenterology : WJG 2004 Nov 1;10(21):3081-7
  6. Yabe D, Brown MS, Goldstein JL
    Insig-2, a second endoplasmic reticulum protein that binds SCAP and blocks export of sterol regulatory element-binding proteins. Proceedings of the National Academy of Sciences of the United States of America 2002 Oct 1;99(20):12753-8
  7. Osborne TF
    Sterol regulatory element-binding proteins (SREBPs): key regulators of nutritional homeostasis and insulin action. The Journal of biological chemistry 2000 Oct 20;275(42):32379-82
  8. Daniel S, Kim KH
    Sp1 mediates glucose activation of the acetyl-CoA carboxylase promoter. The Journal of biological chemistry 1996 Jan 19;271(3):1385-92
  9. Moon YA, Kim KS, Cho UH, Yoon DJ, Park SW
    Characterization of regulatory elements on the promoter region of human ATP-citrate lyase. Experimental & molecular medicine 1999 Jun 30;31(2):108-14
  10. Xiong S, Chirala SS, Wakil SJ
    Sterol regulation of human fatty acid synthase promoter I requires nuclear factor-Y- and Sp-1-binding sites. Proceedings of the National Academy of Sciences of the United States of America 2000 Apr 11;97(8):3948-53
  11. Moon YA, Shah NA, Mohapatra S, Warrington JA, Horton JD
    Identification of a mammalian long chain fatty acyl elongase regulated by sterol regulatory element-binding proteins. The Journal of biological chemistry 2001 Nov 30;276(48):45358-66

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