Finally, SREBP-1c activates three genes required to generate nicotinamide adenine dinucleotide phosphate, which is consumed at several stages of these lipid biosynthesis pathways.[16] Many of these
target genes have been observed to be downregulated in the livers of obese rats when treated with the CB1R inverse agonist rimonabant.[23] SREBP expression is regulated at both a transcriptional and a post-transcriptional level. The post-transcriptional regulation involves the sterol-mediated inhibition of SREBP cleavage, which stops SREBP from reaching the nucleus and affecting gene transcription.[16] SREBP can also be degraded proteasomally after ubiquitination by Fbw7.[24] The transcriptional regulation of SREBP is discussed below. Liver X-activated receptors (LXR), insulin and glucagon regulate the transcription Palbociclib ic50 of SREBP-1c. LXR are transcription factors that form heterodimers with retinoid X receptors and are activated by sterols. They exist in two isoforms, LXRα and LXRβ, and bind to the SREBP-1c promoter region where they activate transcription in the presence of LXR agonists.[25] Treatment of hepatocytes with rimonabant decreased activation of LXR target genes after exposure to a synthetic
LXRα agonist,[26] suggesting that activation of SREBP-1c by CB1R is mediated by LXRα. Liver X-activated receptor-α is inhibited by direct phosphorylation by protein kinase A (PKA),[27] which is activated
by elevated cytosolic MCE cyclic AZD6244 adenosine monophosphate (cAMP) levels.[28] Rimonabant has been shown to increase PKA activity by raising cAMP levels.[26] G proteins of the Gαi/o family that are coupled to CB1R probably depress cAMP production by inhibiting adenylyl cyclase.[29] Together, these results show that Gαi/o proteins coupled to CB1R inhibit adenylyl cyclase, lower cytosolic cAMP, which inhibits PKA, which activates LXR, which increases SREBP-1c transcription. Insulin activates the phosphatidylinositol 3-kinase (PI3K) pathway, which leads to an increase of the precursor form of SREBP-1c in endoplasmic reticulum (ER). This precursor form is then rapidly cleaved, increasing the content of the nuclear mature form of SREBP-1c.[30] Moreover, a high glucose concentration has been shown in vitro to stimulate SREBP-1c expression independently of insulin.[31] Glucagon opposes the effects of insulin and raises intracellular cAMP levels; incubating primary hepatocytes with glucagon or the cell-permeable cAMP analog dibutyryl cAMP decreases mRNA for SREBP-1c and its target lipogenic genes.[32] Glucagon receptor stimulation has been found to be critical for exercise-stimulated reversal of high-fat diet-induced fatty liver in mice.
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