Schoenheimer effect explained – feedback regulation of cholesterol synthesis in mice mediated by Insig proteins
Luke J. Engelking, Guosheng Liang, Robert E. Hammer, Kiyosumi Takaishi, Hiroshi Kuriyama, Bret M. Evers, Wei-Ping Li, Jay D. Horton, Joseph L. Goldstein, Michael S. Brown
Luke J. Engelking, Guosheng Liang, Robert E. Hammer, Kiyosumi Takaishi, Hiroshi Kuriyama, Bret M. Evers, Wei-Ping Li, Jay D. Horton, Joseph L. Goldstein, Michael S. Brown
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Research Article Metabolism

Schoenheimer effect explained – feedback regulation of cholesterol synthesis in mice mediated by Insig proteins

Abstract

End-product feedback inhibition of cholesterol synthesis was first demonstrated in living animals by Schoenheimer 72 years ago. Current studies define Insig proteins as essential elements of this feedback system in mouse liver. In cultured cells, Insig proteins are required for sterol-mediated inhibition of the processing of sterol regulatory element–binding proteins (SREBPs) to their nuclear forms. We produced mice with germline disruption of the Insig2 gene and Cre-mediated disruption of the Insig1 gene in liver. On a chow diet, these double-knockout mice overaccumulated cholesterol and triglycerides in liver. Despite this accumulation, levels of nuclear SREBPs and mRNAs for SREBP target genes in lipogenic pathways were not reduced. Whereas cholesterol feeding reduced nuclear SREBPs and lipogenic mRNAs in wild-type mice, this feedback response was severely blunted in the double-knockout mice, and synthesis of cholesterol and fatty acids was not repressed. The amount of HMG-CoA reductase protein was elevated out of proportion to the mRNA in the double-knockout mice, apparently owing to the failure of cholesterol to accelerate degradation of the enzyme. These studies indicate that the essential elements of the regulatory pathway for lipid synthesis function in liver as they do in cultured cells.

Authors

Luke J. Engelking, Guosheng Liang, Robert E. Hammer, Kiyosumi Takaishi, Hiroshi Kuriyama, Bret M. Evers, Wei-Ping Li, Jay D. Horton, Joseph L. Goldstein, Michael S. Brown

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Lipid accumulation in livers of L-Insig1–/–Insig2–/– mice. Adult female ...
Lipid accumulation in livers of L-Insig1–/–Insig2–/– mice. Adult female mice were treated with 4 intraperitoneal injections of pIpC (300 μg/injection), and the livers were removed either 12 days (A and B) or 7 days (C and D) after the final injection. (A and B) Photographs of livers from chow-fed control and L-Insig1–/–Insig2–/– mice. (C and D) Oil red O–stained histologic sections of the livers from chow-fed control (left) and L-Insig1–/–Insig2–/– mice. Mice were perfused through the heart with HBSS and then with 10% (v/v) formalin in PBS; frozen sections of livers were stained with oil red O. Magnification, ×20.