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
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