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This first part will focus on both on basic gene transcription as an introduction to the production and eventual functions of the SREBP-1c protein.

The Sterol Regulatory Element Binding Proteins (SREBP) are transcription factors, which strongly influence lipid metabolism. They exist in three forms – SREBP-1c, also known as adipocyte determination and differentiation factor 1 (ADD1), and SREBP-1a, which are derived from the same gene [1]. SREBP-1 variants mainly affect lipogenic processes, or those that are able to form adipose tissue [1,2,3,4]

The third member, SREBP-2, born from a separate gene, is an important regulator of cholesterol synthesis and uptake. This work will focus on SREBP-1c, which has little to no effect on cholesterol synthesis [2]. While SREBP-1a accelerates transcription rates more so than 1c, it is the 1c version that is found in greater abundance in humans, especially in hepatic and adipose tissues, the major sites of lipid metabolism [1].

As SREBP-1c works through DNA interplay, it is important to have an understanding of what an operon is. Essentially it is the portion of the DNA molecule containing distinct regions, which control the expression of a gene. It has a promoter region which binds RNA polymerase, a requirement for the initiation of transcription of the operon’s target protein. When RNA polymerase is bound to the promoter, transcription, or the transfer of DNA material into the form of messenger RNA, can occur.

Activators aid in this process, by interacting with enhancer regions called response elements (RE). RE’s can be located adjacent to or relatively far away from both the promoter and operon unit. Binding of an activator to its RE allows RNA polymerase to bind to its promoter, thus turning the operon and gene expression “on”. For SREBP-1c to be “made”, several substances, including the liver-x-receptor (LXR), glucose, and insulin work as activators. It is important to note that these are activators that promote the transcription of SREBP-1c itself. Once produced and functional, then, SREBP-1c also works as an activator in the manufacturing of lipogenic and gluconeogenic enzymes.

This might seem confusing but in short:

  • Activators enhance transcription of a protein and/or enzyme
  • Glucose, insulin, etc are activators for the SREBP-1c protein and bind to response elements that promote SREBP-1c’s transcription
  • SREBP-1c’s later act as activators themselves by binding to response elements that promote transcription of adipogenic and gluconeogenic enzymes and proteins

A side note that should be considered here is that activators can produce transcription enhancing proteins which expedite RNA polymerase/promoter contact.

The operon also contains the operator region, which can bind to repressor proteins and prevent transcription. The operator typically lies adjacent to or physically overlaps the promoter. This repressor-operator complex often acts by blocking RNA polymerase from binding to its promoter, leaving the operon “off”.

SREBP-1c is an activator thus supporting positive gene regulation. One of its targets is the Sterol Response element-1 (SRE-1), which binds proteins involved in triglyceride and cholesterol synthesis. SRE also aids in the production of the SREBP-1c itself. So as we can see, SRE creates a protein, which it can later interact with to induce lipid enzyme production.

The promoter region for the development of SREBP-1c has several regulatory controls apart from SRE-1.


Liver X Receptor (LXR), located in the nucleus of liver cells, upregulates SREBP-1c transcription [5,6]. LXR forms a complex with the Retinoid X Receptor (RXR), which is required for its interaction with Liver X response elements (LXRE)[5,6,7]. LXRE are enhancer regions, located within the actual SREBP-1c promoter [8] that bind LXR-RXR, which then acts as an activator of the 1c variant transcription [5,6,7]. LXR forms a complex with the Retinoid X Receptor (RXR), which is required for its interaction with Liver X response elements (LXRE) [5,6,7]. Agonists of LXR increase mRNA of SREBP-1c but have no impact on their SREBP-1a and 2 counterparts [6,7]. This further lends evidence to the claim that the 1c version is the most potent target of LXR in elevating lipogenic enzymes [2].

While the LXR-RXR is a strong player in SREBP-1c production, insulin is the key player. SREBP1-c mRNA is elevated during hyperinsulinemia conditions and when cultured hepatocytes are exposed to insulin [9,10]. In fact, the potency of LXR-RXR is greatly reduced in the absence of insulin as it does not have the capacity to cleave the precursor to mature SREBP-1c so 1c remains attached to and in essence idle in the endoplasmic reticulum (ER) [10,11].

You see once SREBP’s have been transcribed they are attached to either the nuclear envelope or the rough endoplasmic reticulum (ER) with their carboxycylic acid, or C-terminus side, and its Amino (NH2), or N-terminus side extending outside the ER into the cytoplasm. Within the ER, SREBP’s are bound to SREBP cleavage activating proteins (SCAP). When low sterol levels, such as cholesterol and/or lipids, are experienced inside the cell, the SCAP transports SREBP’s to the golgi apparatus [12]. There they must be subjected to post-transcription processing via proteolytic cleavage of both their N-terminus and C-terminus sides to “mature” into fully functional proteins [10,11]. Only then can the SREBP move through the cell to the nucleus to interact with specific segments of DNA, the SRE, to promote transcription [12]. This process is enhanced in the presence of insulin [10,11]. Thus, both the transcription and ultimate activation of SREBP are influenced by insulin. This would be an example of a negative feedback loop as low levels of sterols in the cell “tell” the DNA to enhance its production of lipid and lipid metabolizing enzymes to re-establish a homeostasis of sorts.

Upon overfeeding, insulin is elevated which creates a surplus of energy substrates that overwhelm the oxidizing capacity of the mitochondria. What ensues is the conversion of unused and incompletely oxidized substrates into precursors for triglyceride synthesis. One of the means by which insulin upregulates this process is through its control of SREBP-1c production.

Working in concert with insulin, SREBP-1c induces a plethora of lipid synthesizing enzymes including acetyl-coenzyme A carboxylase (ACC), ATP-citrate lyase, glucose 6-phosphate dehydrogenase (G6PDH), and 6-phosphogluconate dehydrogenase (6PGDH) [1,11,12]. Fatty Acid Synthase (FAS) is the primary target protein of SREBP-1c and working in tandem with the aforementioned lipogenic enzymes facilitates the conversion of Acetyl-CoA and Maylonyl-CoA into palmitate. This is a key step in triacylglycerol (TAG) synthesis, as 3 palmitates are attached to 3 glycerols, forming a TAG, the building blocks of fat tissue [13].

The recent attacks targeting high-carbohydrate diets seem to be gaining more scientific backing and its deleterious impact on SREBP-1c elevation further substantiates these recommendations. In fact, high glucose levels attained through high carbohydrate diets can positively augment SREBP-1c activity independent of insulin [14,15]. In rats with artificially reduced insulin levels, glucose caused an even greater SREBP-1c response than a matched group with normal insulin levels exposed to glucose (28). Fructose and sucrose were administered in the same fashion and also produced similar results albeit less than glucose. It is of note that the glycemic indexes (GI) of these three sugars directly correlated with the rate at which SREBP-1c mRNA was identified. GI measures the rate of change in blood glucose levels following the consumption of a given carbohydrate source. Dextrose (glucose), having the highest GI (100) produced the quickest rise in mRNA activity, while fructose, having the lowest GI, was slowest in this regard. Sucrose, a disaccharide of fructose and glucose with a modest GI, performed in between the other two sugars relative to its SREBP-1c transcription rates [28].


In terms of its effects of gluconeogenesis, over expression of SREBP-1c has been shown to reduce gluconeogenic enzymes, including Phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase [16]. Working in concert with pyruvate carboxylase, PEPCK induces the conversion of oxaloacetate to phosphoenolpyruvate. This activity is called upon when excess acetyl groups need to be exported from the mitochondria. Gluconeogenesis ensues to maintain normal blood glucose levels under fasting conditions. PEPCK also accelerates a rarely discussed process, termed Glyceroneogenesis. This pathway is involved in the de novo synthesis of glycerol-3-phosphate, which can eventually be converted to fatty acids for reincorporation into triglycerides [17]. This is advantageous in diabetic conditions, as it maintains a low level of free fatty acids. However, in healthy non-diabetic individuals, this process simply discourages beta oxidation and makes one more prone to maintain current bodyfat levels.

So in this regard SREBP-1c’s suppression of PEPCK indirectly has an anti-lipogenic affect, allowing for the opportunity free fatty acids to be oxidized rather than re-esterified. Assuming triglyceride hydrolysis has occurred SREBP-1c then does not directly hinder ‘fat burning’ per se.

The take-home message, though, is that SREBP-1c is not your friend whether trying to maintain current bodyfat levels while taking in above maintenance calories nor when one is attempting to induce reductions in bodyfat through a hypocaloric intake.

The next installment in this series will discuss how one can utilize several different nutrition and supplementation techniques to keep SREBP-1c in check.


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2. 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.
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8. Yoshikawa T, Shimano H, Amemiya-Kudo M, Yahagi N, Hasty AH, Matsuzaka T, Okazaki H, Tamura Y,
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