[HTML][HTML] SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver

JD Horton, JL Goldstein… - The Journal of clinical …, 2002 - Am Soc Clin Investig
JD Horton, JL Goldstein, MS Brown
The Journal of clinical investigation, 2002Am Soc Clin Investig
SPOTLIGHT Critical review thesis. Like SREBP-1a, SREBP-2 has a long transcriptional
activation domain, but it preferentially activates cholesterol synthesis (1). SREBP-1a and
SREBP-2 are the predominant isoforms of SREBP in most cultured cell lines, whereas
SREBP-1c and SREBP-2 predominate in the liver and most other intact tissues (6). When
expressed at higher than physiologic levels, each of the three SREBP isoforms can activate
all enzymes indicated in Figure 2, which shows the biosynthetic pathways used to generate …
SPOTLIGHT Critical review thesis. Like SREBP-1a, SREBP-2 has a long transcriptional activation domain, but it preferentially activates cholesterol synthesis (1). SREBP-1a and SREBP-2 are the predominant isoforms of SREBP in most cultured cell lines, whereas SREBP-1c and SREBP-2 predominate in the liver and most other intact tissues (6). When expressed at higher than physiologic levels, each of the three SREBP isoforms can activate all enzymes indicated in Figure 2, which shows the biosynthetic pathways used to generate cholesterol and fatty acids. However, at normal levels of expression, SREBP-1c favors the fatty acid biosynthetic pathway and SREBP-2 favors cholesterologenesis. SREBP-2–responsive genes in the cholesterol biosynthetic pathway include those for the enzymes HMG-CoA synthase, HMG-CoA reductase, farnesyl diphosphate synthase, and squalene synthase. SREBP-1c–responsive genes include those for ATP citrate lyase (which produces acetyl-CoA) and acetyl-CoA carboxylase and fatty acid synthase (which together produce palmitate [C16: 0]). Other SREBP-1c target genes encode a ratelimiting enzyme of the fatty acid elongase complex, which converts palmitate to stearate (C18: 0)(ref. 7); stearoyl-CoA desaturase, which converts stearate to oleate (C18: 1); and glycerol-3-phosphate acyltransferase, the first committed enzyme in triglyceride and phospholipid synthesis (3). Finally, SREBP-1c and SREBP-2 activate three genes required to generate
The Journal of Clinical Investigation