While Cho et al. have written a modern article in regard to hepatic SREBP1a, it may well be that Rong et al. (“Horton Lab”) have done everything to maintain the conventional view about SREBP1c and SREBP1a in hepatic lipogenesis.

*** First article: Cho et al. ***

ENOblock, a unique small molecule inhibitor of the non-glycolytic functions of enolase, alleviates the symptoms of type 2 diabetes. Sci Rep. 2017 Mar 8;7:44186.

Statements:

»…the 12 mg/kg ENOblock treatment decreased the serum level of free fatty acid compared to untreated db/db mice (Fig. 2G). This could be due to the observed inhibition of Srebp-1a and -1c, which are key regulators of lipid homeostasis.«

»ENOblock treatment normalized Srebp-1a expression to the level observed in normal B6 mice and also reduced the expression of Srebp-1c (Fig. 3R,S).«

*** Second article: Rong et al. ***

Expression of SREBP-1c Requires SREBP-2-mediated Generation of a Sterol Ligand for LXR in Livers of Mice. Elife. 2017 Feb 28;6. pii: e25015.

The following statements must be considered very critically:

• Statement 1: »Expression of SREBP-1c Requires SREBP-2-mediated Generation of a Sterol Ligand for LXR in Livers of Mice.« (The title of this article)

• Statement 2: »The only molecular signature we found that differed between hepatocyte-Srebf-2^-/- and hepatocyte-Scap^-/- livers was the retained expression of SREBP-1a and ACC2 in the livers of hepatocyte-Srebf-2^-/- mice. These studies confirm that SREBP-1a has only a minor role in regulating basal and stimulated cholesterol and fatty acid synthesis in the liver.«

Evaluation of statement 1:

In my opinion, the title is not supported by the results – Au contraire:

1. They have examined liver tissue extracts for a possible endogenous sterol LXR ligand whose concentration is greatly reduced in hepatocyte-Srebf-2^-/- livers. However, they have not found any. In contrast, the liver tissue concentrations of the potent endogenous sterol LXR ligands desmosterol (Ref. 1) and 24,25-epoxycholesterol (Ref. 2; and references therein) were elevated 3-fold and 7-fold, respectively, in hepatocyte-Srebf-2^-/- livers of 12-13 week-old mice (see here).
2. The studies with T0901317 and 0,2% Cholesterol are far from being sufficient in order to support the conclusion/title of this article. (I will get back to this topic in more detail soon; see section »PXR versus LXR«)

Evaluation of statement 2:

1. As they have already written in the Results section: »…ACC2 expression, which is primarily regulated by SREBP-1a, was only slightly (-30%) lower (in hepatocyte-Srebf-2^-/- livers).« Furthermore, in SREBP1a-deficient mice and SREBP1a-deficient human hepatocytes, ACC2 mRNA expression is only 40-50% lower (Ref. 3, Ref. 4).
2. ACC2 was only 40% lower in S1P-inhibited human hepatocytes (Ref. 4). (Inhibition of S1P blocks the proteolytic activation of SREBP proteins)
3. ACC2 was not measured in livers of mice that lack Scap in hepatocytes (Ref. 5, Ref. 6 and this article).
4. Beside the lower mRNA expression of SREBP1a in hepatocyte-Srebf-2^-/- livers (-20%; see here), they do not mention the 40% and 70% reduced hepatic SREBP1a mRNA level in hypomorphic SREBP-2 and Srebf-2^-/- mice which was observed by Vergnes et al. (Ref. 7). Furthermore, the reduced mRNA expression of SREBP1a in livers of hepatocyte-Srebf-2^-/- mice gives no indication of whether there is an even more pronounced reduction in the amount of the mature SREBP1a protein. (Also see section »SREBP1a«)