Inhibition of SREBP by a Small Molecule, Betulin, Improves Hyperlipidemia and Insulin Resistance and Reduces Atherosclerotic Plaques

Abstract

Sterol regulatory element-binding proteins (SREBPs) are major transcription factors activating the expression of genes involved in biosynthesis of cholesterol, fatty acid and triglyceride. In this study, we identified a small molecule, betulin, that specifically inhibited the maturation of SREBP by inducing interaction of SREBP cleavage activating protein (SCAP) and Insig. Inhibition of SREBP by betulin decreased the biosynthesis of cholesterol and fatty acid. In vivo, betulin ameliorated diet-induced obesity, decreased the lipid contents in serum and tissues, and increased insulin sensitivity. Furthermore, betulin reduced the size and improved the stability of atherosclerotic plaques. Our study demonstrates that inhibition SREBP pathway can be employed as a therapeutic strategy to treat metabolic diseases including type II diabetes and atherosclerosis. Betulin, which is abundant in birch bark, could be a leading compound for development of drugs for hyperlipidemia.

2-(3-Benzoylthioureido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid ameliorates metabolic disorders in high-fat diet-fed mice

“…Consistent with previous reports [34][35][36] , we observed that the mRNA levels of SREBP-1c and SREBP-2, and their target genes, were increased in the liver of long-term high-fat-dietfed mice. The beneficial effects of ZJ001 on metabolic parameters were reflected by its effects on gene expression changes in the liver of mice.…”

“…Decreased cholesterol biosynthesis increases LDL-receptor levels, which results in a positive cycle for lowered cholesterol levels in serum. However, statins cannot decrease fatty acid biosynthesis because they block the cholesterol biosynthesis that stimulates SREBP activity [36] . The above deficiency of the statin drugs might be compensated for if candidates that specifically modulate the SREBP pathway are identified.…”

Exercise training prevents skeletal muscle plasma membrane cholesterol accumulation, cortical actin filament loss, and insulin resistance in C57BL/6J mice fed a western-style high-fat diet

“…In support of this possibility, inhibition of SREBP was found to ameliorate diet‐induced cholesterol/lipid tissue accumulation and insulin resistance (Tang et al. 2011). …”

The N-terminal Domain of NPC1L1 Protein Binds Cholesterol and Plays Essential Roles in Cholesterol Uptake

“…Animal protocols and adenovirus-mediated expression of EGFP, NPC1L1-EGFP, NPC1L1⌬NTD-EGFP, and NPC1L1(L216A)-EGFP in mice liver as well as measurement of cholesterol, phospholipid, or triglyceride in the bile, liver, or plasma were described previously (7,21 (15,18,19). Briefly, HEK293T cells were grown in a monolayer at 37°C in 5% CO 2 .…”