Figure 6. Sesn1 has a liver-specific role and regulates cholesterol biosynthesis.

(A) Plasma total cholesterol levels change in three days cholesterol diet fed Alb-cre⁻/Sesn^fl/wt (black) and Alb-cre⁺/Sesn^fl/wt male mice (red). n > 6.

(B) Plasma total cholesterol levels in random fed, fasted, and high-carbohydrate diet refed Alb-cre⁻/Sesn^fl/wt (white), Alb-cre⁺/Sesn^fl/wt (black) and Alb-cre⁺/Sesn^fl/fl (red) female mice (red). n > 3. (C) Plasma total cholesterol levels in Sesn1^+/+ (black), Sesn1^+/− (red), and Sesn1^−/−(blue) mice before and after lovastatin treatment. Mice were fed a cholesterol diet three days. n > 4.

(D) Quantification of total cellular cholesterol levels in AML12 cells after Sesn1 silencing (red) or control (black), with mevastatin. n = 4.

(E) mRNA expression levels in control siRNA (white or black bars) or Sesn1 siRNA (gray or red bars) treated AML12 cells with mevastatin. n = 3.

(F) Measurement of incorporation of radiolabeled 14C-acetate into cholesterol in AML12 cells after Sesn1 silencing (red) or control (black).

(G) Liver protein expression levels and quantification of AMP kinase (AMPK), phosphorylated AMPK, acetyl-CoA carboxylase (ACC) and phosphorylated ACC in Sesn1^+/+ and Sesn1^−/− mice fed cholesterol diet for 12 weeks.

(H) Cholesterol biosynthesis is controlled by a feedback inhibition mechanism primarily through the action of Insig1 (Insulin induced gene 1). Under cholesterol depletion, SREBP2 is activated for transcriptional activated of cholesterol biosynthesis by HMGCR and/or cholesterol uptake by LDLR, termed as cholesterol regulation (red line). Insig1 is up-regulated, leading to retention of the Scap-SREBP complex and causing SREBP2 inactivation. This is called cholesterol feedback inhibition (blue line). In our study, Sesn1, was found to be a target of SREBP2, and can also inhibit cholesterol biosynthesis. Our finding establishes Sesn1 as a regulator of cholesterol feedback inhibition

Data represented is mean ± SE, **P < 0.01, *P < 0.05.