Regulation of Cholesterol and Fatty Acid Synthesis

Jin, Yufeng; DeBose‐Boyd, Russell A.

doi:10.1101/cshperspect.a004754

Cited by 203 publications

(158 citation statements)

References 59 publications

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“…To test the effect of intestinal Insig deficiency on in vivo lipid synthesis, we next measured the incorporation of intraperitoneally injected 3 H-labeled water into digitonin-precipitable sterols and fatty acids in control and Vil-Insig ؊ mice (Fig. 3).…”

Section: Resultsmentioning

confidence: 99%

“…Rates-Rates of cholesterol and fatty acid synthesis were measured in mice using 3 H-labeled water as described previously (25). The mice were fed ad libitum with chow diets and then fasted for 4 h prior to injection of 3 H-labeled water.…”

Section: Measurement Of In Vivo Cholesterol and Fatty Acid Synthesismentioning

confidence: 99%

“…Insig1 and Insig2 are two closely-related endoplasmic reticulum (ER) 3 membrane proteins essential for feedback inhibition of cholesterol synthesis in cultured cells and in the liver. Insig proteins mediate this regulation by virtue of their steroldependent interaction with two other ER membrane proteins: Scap, an escort protein required for the proteolytic processing and activation of sterol regulatory element-binding proteins (SREBPs), and HMG-CoA reductase (HMGR), the enzyme that catalyzes the rate-determining step of the cholesterol biosynthetic pathway.…”

mentioning

confidence: 99%

“…When cells are depleted of sterols, SREBPs are transported by Scap from ER to Golgi, where they are processed proteolytically to yield active nuclear fragments (nSREBPs). Sterol-induced binding of Insig to Scap leads to retention of the Scap-SREBP complex in ER, thereby preventing the proteolytic processing of SREBPs to their active nuclear forms (2,3). Sterol-induced binding of Insigs to HMGR leads to its ubiquitination and proteasomal degradation (4,5).…”

mentioning

confidence: 99%

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Insig Proteins Mediate Feedback Inhibition of Cholesterol Synthesis in the Intestine

McFarlane

Liang

Engelking

2014

Journal of Biological Chemistry

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Section: Resultsmentioning

confidence: 99%

Section: Measurement Of In Vivo Cholesterol and Fatty Acid Synthesismentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Insig Proteins Mediate Feedback Inhibition of Cholesterol Synthesis in the Intestine

McFarlane

Liang

Engelking

2014

Journal of Biological Chemistry

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“…However, only recently have the mechanisms that ensure sphingolipid homeostasis begun to be identified. Here a sharp contrast can be seen with the many regulatory pathways identified for sterols and glycerolipids (Nohturfft and Zhang 2009;Ye and DeBose-Boyd 2011). For instance, elegant studies have shown that cholesterol metabolism is controlled by multiple feedback mechanisms, including transcriptional regulation by SREBP, degradation of HMG-CoA reductase, and turnover of the LDL receptor responsible for cholesterol uptake (Chang et al 2006;Brown and Goldstein 2009).…”

Section: Mechanisms Of Sphingolipid Homeostasismentioning

confidence: 99%

Sphingolipid Homeostasis in the Endoplasmic Reticulum and Beyond

Breslow

2013

Cold Spring Harbor Perspectives in Biology

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Sphingolipids are a diverse group of lipids that have essential cellular roles as structural components of membranes and as potent signaling molecules. In recent years, a detailed picture has emerged of the basic biochemistry of sphingolipids-from their initial synthesis in the endoplasmic reticulum (ER), to their elaboration into complex glycosphingolipids, to their turnover and degradation. However, our understanding of how sphingolipid metabolism is regulated in response to metabolic demand and physiologic cues remains incomplete. Here I discuss new insights into the mechanisms that ensure sphingolipid homeostasis, with an emphasis on the ER as a critical regulatory site in sphingolipid metabolism. In particular, Orm family proteins have recently emerged as key ER-localized mediators of sphingolipid homeostasis. A detailed understanding of how cells sense and control sphingolipid production promises to provide key insights into membrane function in health and disease.

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Human carotid atherosclerotic lesion protein components decrease cholesterol biosynthesis rate in macrophages through 3‐hydroxy‐3‐methylglutaryl‐CoA reductase regulation

et al. 2015

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Atherosclerosis is characterized by the formation of cholesterol-loaded macrophages, which are turned into foam cells, the hallmark of early atherogenesis. As part of ongoing research on the interactions among human carotid lesion components and blood elements, the effect of plaque homogenate on macrophage cholesterol biosynthesis rate was examined. Human carotid plaques were ground, extracted with phosphate-buffered saline (homogenate), and then added to the macrophage medium. This extract decreased macrophage cholesterol biosynthesis rate up to 50% in a dose-dependent manner. Cholesterol or lipoproteins were separated from the homogenate and added to the MQ medium. Unlike the homogenate, neither free cholesterol nor the lipoproteins were able to inhibit cholesterol biosynthesis rate under the above experimental concentration, suggesting that the homogenate-induced cholesterol biosynthesis inhibition in our experimental system was not owing to the feedback inhibition of cholesterol. Furthermore, the homogenate remaining after lipoprotein removal (lipoprotein-deficient homogenate) also decreased cholesterol biosynthesis rate, whereas boiled homogenate or phospholipids extracted from the homogenate decreased macrophage cholesterol biosynthesis rate only partially. Finally, cholesterol biosynthesis inhibition was achieved only upon using the precursor [(3)H]acetate, but not [(14)C]mevalonate, suggesting that 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCoA Reductase), the rate-limiting enzyme in the cholesterol biosynthesis pathway, is involved in the above antiatherogenic effect of the homogenate, whereas the treatment with homogenate decreased HMGCoA Reductase mRNA. Proteins and phospholipids from human carotid lesion homogenate decrease cholesterol biosynthesis rate in macrophages secondary to HMGCoA Reductase feedback regulation. Such an effect may delay foam cell formation and atherosclerosis progression.

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Regulation of Cholesterol and Fatty Acid Synthesis

Cited by 203 publications

References 59 publications

Insig Proteins Mediate Feedback Inhibition of Cholesterol Synthesis in the Intestine

Insig Proteins Mediate Feedback Inhibition of Cholesterol Synthesis in the Intestine

Sphingolipid Homeostasis in the Endoplasmic Reticulum and Beyond

Human carotid atherosclerotic lesion protein components decrease cholesterol biosynthesis rate in macrophages through 3‐hydroxy‐3‐methylglutaryl‐CoA reductase regulation

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