Short Introduction
»The transcription factor sterol regulatory element-binding protein 1 (SREBP1) was recognized as the master regulator of de novo lipogenesis, especially regulating genes encoding key enzymes of fatty acid and triglyceride biosynthesis in the liver [1]. An increase in de novo lipogenesis was recently shown to substantially contribute to the excess storage of triglycerides in non-alcoholic fatty liver disease (NAFLD) [2], which encompasses a spectrum of diseases ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). While numerous reports showed up-regulation of SREBP1 in human NAFLD [3], studies with SREBP1-transgenic mice [4, 5] and of SREBP1 knock-out or knockdown in murine NAFLD disease models [6, 7] further confirmed the crucial role of the gene in hepatic steatosis.
In mammals, two isoforms of SREBP1 protein, SREBP1a and SREBP1c, are known, which arise by the use of two alternative first exons (both transcripts produced from the same SREBF1 gene through the use of alternate promoters). Exon 1a encodes the unique 29 amino acids of the SREBP1a NH2-terminus, whereas exon 1c only encodes 5 unique amino acids [8]. Thus, the NH2-terminal acidic transcriptional activation domain of SREBP1a is 24 amino acids longer and harbors 12 negatively charged amino acids, whereas the respective domain of SREBP1c contains only 6 negatively charged residues [9]. Consequently, SREBP1a proved to be the by far stronger transcriptional activator of the two isoforms, both in vitro [10] and in vivo [11].
It is believed that SREBP1c, which is the dominant isoform in many mouse tissues, including liver [8], is mediating the nutritional control of hepatic lipogenic gene expression [12], as, for example, its expression [13] and proteolytic activation [14] are induced by insulin signaling. Thus, it is the isoform which has been implicated in NAFLD.
In contrast, the physiological and pathophysiological role of SREBP1a in the liver is less well understood. SREBP1a is commonly regarded as being negligible in liver, as it was previously shown in mice to be expressed at 9-fold lower levels than SREBP1c [8]. It was further shown that 1a is 6-fold outnumbered by 1c in human liver, which however was based only on the analysis of an individual liver sample [8].«
[Bitter et al. Human sterol regulatory element-binding protein 1a contributes significantly to hepatic lipogenic gene expression. Cell Physiol Biochem. 2015;35(2):803-15.]
But there are impressive contradictions regarding the highly questionable physiological (nutritional regulation) and pathophysiological (e.g., NAFLD/NASH, diabetes mellitus type 2, viral hepatitis and hepatocarcinoma) role of SREBP1c in hepatic lipid metabolism.
What about SREBP1a
References
[1] Horton JD, Goldstein JL, Brown MS: SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest 2002;109:1125-1131.
[2] Lambert JE, Ramos-Roman MA, Browning JD, Parks EJ: Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease. Gastroenterology 2014;146:726-735.
[3] Pettinelli P, Videla LA: Up-regulation of PPAR-gamma mRNA expression in the liver of obese patients: an additional reinforcing lipogenic mechanism to SREBP-1c induction. J Clin Endocrinol Metab 2011;96:1424-1430.
[4] Shimano H, Horton JD, Hammer RE, Shimomura I, Brown MS, Goldstein JL: Overproduction of cholesterol and fatty acids causes massive liver enlargement in transgenic mice expressing truncated SREBP-1a. J Clin Invest 1996;98:1575-1584.
[5] Knebel B, Haas J, Hartwig S, Jacob S, Köllmer C, Nitzgen U, Muller-Wieland D, Kotzka J: Liver-specific expression of transcriptionally active SREBP-1c is associated with fatty liver and increased visceral fat mass. PLoS One 2012;7:e31812.
[6] Yahagi N, Shimano H, Hasty AH, Matsuzaka T, Ide T, Yoshikawa T, Amemiya-Kudo M, Tomita S, Okazaki H, Tamura Y, Iizuka Y, Ohashi K, Osuga J, Harada K, Gotoda T, Nagai R, Ishibashi S, Yamada N: Absence of sterol regulatory element-binding protein-1 (SREBP-1) ameliorates fatty livers but not obesity or insulin resistance in Lep(ob)/Lep(ob) mice. J Biol Chem 2002;277:19353-19357.
[7] Frederico MJ, Vitto MF, Cesconetto PA, Engelmann J, De Souza DR, Luz G, Pinho RA, Ropelle ER, Cintra DE, De Souza CT: Short-term inhibition of SREBP-1c expression reverses diet-induced non-alcoholic fatty liver disease in mice. Scand J Gastroenterol 2011;46:1381-1388. SREBP-1c or SREBP-1a?
[8] Shimomura I, Shimano H, Horton JD, Goldstein JL, Brown MS: Differential expression of exons 1a and 1c in mRNAs for sterol regulatory element binding protein-1 in human and mouse organs and cultured cells. J Clin Invest 1997;99:838-845.
[9] Brown MS, Goldstein JL: The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 1997;89:331-340.
[10] Amemiya-Kudo M, Shimano H, Hasty AH, Yahagi N, Yoshikawa T, Matsuzaka T, Okazaki H, Tamura Y, Iizuka Y, Ohashi K, Osuga J, Harada K, Gotoda T, Sato R, Kimura S, Ishibashi S, Yamada N: Transcriptional activities of nuclear SREBP-1a, -1c, and -2 to different target promoters of lipogenic and cholesterogenic genes. J Lipid Res 2002;43:1220-1235.
[11] Shimano H, Horton JD, Shimomura I, Hammer RE, Brown MS, Goldstein JL: Isoform 1c of sterol regulatory element binding protein is less active than isoform 1a in livers of transgenic mice and in cultured cells. J Clin Invest 1997;99:846-854.
[12] Shimano H, Yahagi N, Amemiya-Kudo M, Hasty AH, Osuga J, Tamura Y, Shionoiri F, Iizuka Y, Ohashi K, Harada K, Gotoda T, Ishibashi S, Yamada N: Sterol regulatory element-binding protein-1 as a key transcription factor for nutritional induction of lipogenic enzyme genes. J Biol Chem 1999;274:35832-35839.
[13] Horton JD, Bashmakov Y, Shimomura I, Shimano H: Regulation of sterol regulatory element binding proteins in livers of fasted and refed mice. Proc Natl Acad Sci U S A 1998;95:5987-5992.
[14] Yellaturu CR, Deng X, Cagen LM, Wilcox HG, Mansbach CM, Siddiqi SA, Park EA, Raghow R, Elam MB: Insulin enhances post-translational processing of nascent SREBP-1c by promoting its phosphorylation and association with COPII vesicles. J Biol Chem 2009;284:7518-7532.
What about SREBP1a
