Insig-mediated degradation of HMG CoA reductase stimulated by lanosterol, an intermediate in the synthesis of cholesterol

Song, Bao-Liang; Javitt, Norman B.; DeBose‐Boyd, Russell A.

doi:10.1016/j.cmet.2005.01.001

Cited by 244 publications

(244 citation statements)

References 42 publications

Supporting

Mentioning

227

Contrasting

Unclassified

Order By: Relevance

“…HMGCoAR is the rate-limiting enzyme of cholesterol synthesis, yet surprisingly, low cholesterol levels provide only a relatively weak feedback effect on HMGCoAR. 34 HMGCoAR is under highly complex regulation, 35 but a critical regulator is feedback through the direct sterol-sensing of the lanosterol level (Fig. 1).…”

Section: Discussionmentioning

confidence: 99%

“…26 Through a complex, endoplasmic reticulum-based process, low lanosterol signals to decrease proteolysis of HMGCoAR, which results in increased cholesterol synthesis. 26,34 However, in the setting of normal lanosterol levels, such as observed in HCV infection, HMGCoAR proteolysis continues, and cholesterol synthesis is not up-regulated through this important pathway. Thus, with normal lanosterol levels, irrespective of cholesterol levels, the host fails to engage direct-sensing compensatory cholesterol synthesis through the rate-limiting step of HMGCoAR.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Hepatitis C virus selectively perturbs the distal cholesterol synthesis pathway in a genotype-specific manner

et al. 2012

View full text Add to dashboard Cite

Hepatitis C virus (HCV) subverts host cholesterol metabolism for key processes in its lifecycle. How this interference results in the frequently observed, genotype-dependent clinical sequelae of hypocholesterolemia, hepatic steatosis, and insulin resistance (IR) remains incompletely understood. Hypocholesterolemia typically resolves after sustained viral response (SVR), implicating viral interference in host lipid metabolism. Using a targeted cholesterol metabolomic platform we evaluated paired HCV genotype 2 (G2) and G3 patient sera for changes in in vivo HCV sterol pathway metabolites. We compared HCV genotypic differences in baseline metabolites and following antiviral treatment to assess whether sterol perturbation resolved after HCV eradication. We linked these metabolites to IR and urine oxidative stress markers. In paired sera from HCV G2 (n 5 13) and G3 (n 5 20) patients, baseline sterol levels were lower in G3 than G2 for distal metabolites (7-dehyrocholesterol (7DHC) 0.017 versus 0.023 mg/dL; P adj 5 0.0524, cholesterol 140.9 versus 178.7 mg/dL; P adj 5 0.0242) but not the proximal metabolite lanosterol. In HCV G3, SVR resulted in increased levels of distal metabolites (cholesterol [D55.2 mg/dL; P adj 5 0.0015], 7DHC [D0.0075 mg/dL; P adj 5 0.0026], lathosterol [D0.0430 mg/dL P adj 5 0.0405]). In contrast, lanosterol was unchanged after SVR (P 5 0.9515). Conclusion: HCV G3, but not G2, selectively interferes with the late cholesterol synthesis pathway, evidenced by lower distal sterol metabolites and preserved lanosterol levels. This distal interference resolves with SVR. Normal lanosterol levels provide a signal for the continued proteolysis of 3-hydroxyl-3-methylglutaryl coenzyme A reductase, which may undermine other host responses to increase cholesterol synthesis. These data may provide a hypothesis to explain why hypocholesterolemia persists in chronic HCV infection, particularly in HCV G3, and is not overcome by host cholesterol compensatory mechanisms. (HEPATOLOGY 2012;56:49-56)

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Hepatitis C virus selectively perturbs the distal cholesterol synthesis pathway in a genotype-specific manner

et al. 2012

View full text Add to dashboard Cite

show abstract

“…As with the SREBPs and other proteins, HMGR is targeted for degradation once it is ubiquitinated [41,56]. While HMGR can be ubiquinated in the presence of sterol [41], it is further ubiquinated in the presence of both sterol plus geranylgeraniol, implying involvement of a geranylgeranylated protein [57], or plus lanosterol [58]. These more recent data support the observations that maximal suppression of sterol synthesis rates occurs only in the presence of cholesterol plus a mevalonate-derived product [18,59], which may be absent in a tissue in a negative sterol balance and/or proliferating rapidly as during development [49].…”

Section: Hmgr Degradationmentioning

confidence: 99%

Inability to fully suppress sterol synthesis rates with exogenous sterol in embryonic and extraembyronic fetal tissues

Yao

Jenkins

Horn

et al. 2007

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

View full text Add to dashboard Cite

SUMMARYThe requirement for cholesterol is greater in developing tissues (fetus, placenta, and yolk sac) as compared to adult tissues. Here, we compared cholesterol-induced suppression of sterol synthesis rates in the adult liver to the fetal liver, fetal body, placenta, and yolk sac of the Golden Syrian hamster. Sterol synthesis rates were suppressed maximally in non-pregnant adult livers when cholesterol concentrations were increased. In contrast, sterol synthesis rates were suppressed only marginally in fetal livers, fetal bodies, placentas, and yolk sacs when cholesterol concentrations were increased. To begin to elucidate the mechanism responsible for the blunted response of sterol synthesis rates in fetal tissues to exogenous cholesterol, the ratio of sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) to Insig-1 was measured in these same tissues since the ratio of SCAP to the Insigs can impact SREBP processing. The fetal tissues had anywhere from a 2-to 6-fold greater ratio of SCAP to Insig-1 than did the adult liver, suggesting constitutive processing of the SREBPs. As expected, the level of mature, nuclear SREBP-2 was not different in the fetal tissues with different levels of cholesterol whereas it was different in adult livers. These findings indicate that the suppression of sterol synthesis to exogenous sterol is blunted in developing tissues and the lack of response appears to be mediated at least partly through relative levels of Insigs and SCAP.

show abstract

“…5 shows experiments in which we examined whether the D205A mutation also abolishes the ability of Insig-1 to accelerate the degradation of HMG CoA reductase. Studies have shown (5,17) that Insig-mediated degradation is triggered by the combined action of a sterol (25-HC or lanosterol) and a nonsterol isoprenoid (geranylgeraniol) derived from mevalonate. We cotransfected WT CHO-K1 cells with a plasmid encoding WT or the D205A mutant of Insig-1 together with a plasmid encoding the NH 2 -terminal membrane-spanning domain of HMG CoA reductase [HMG CoA reductase(TM1-8)].…”

Section: Figurementioning

confidence: 99%

Juxtamembranous aspartic acid in Insig-1 and Insig-2 is required for cholesterol homeostasis

Gong

Lee

Brown

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Insig-1 and Insig-2 are closely related proteins of the endoplasmic reticulum (ER) that mediate feedback control of cholesterol synthesis by sterol-dependent binding to the following two membrane proteins: the escort protein Scap, thus preventing proteolytic processing of sterol regulatory element-binding proteins; and the cholesterol biosynthetic enzyme 3-hydroxy-3-methylglutaryl CoA reductase, thus inducing the ubiquitination and ER-associated degradation of the enzyme. Here, we report that the conserved Asp-205 in Insig-1, which abuts the fourth transmembrane helix at the cytosolic side of the ER membrane, is essential for its dual function. When Asp-205 was mutated to alanine, the mutant Insig-1 lost the ability to bind to Scap and, thus, was unable to suppress the cleavage of sterol regulatory element-binding proteins. The mutant Insig-1 was ineffective also in accelerating sterol-stimulated degradation of 3-hydroxy-3-methylglutaryl CoA reductase. Alanine substitution of the corresponding aspartic acid in Insig-2 produced the same dual defects. These studies identify a single amino acid residue that is crucial for the function of Insig proteins in regulating cholesterol homeostasis in mammalian cells.25-hydroxycholesterol ͉ lanosterol ͉ membrane proteins ͉ proteolytic activation ͉ Scap

show abstract

Insig-mediated degradation of HMG CoA reductase stimulated by lanosterol, an intermediate in the synthesis of cholesterol

Cited by 244 publications

References 42 publications

Hepatitis C virus selectively perturbs the distal cholesterol synthesis pathway in a genotype-specific manner

Hepatitis C virus selectively perturbs the distal cholesterol synthesis pathway in a genotype-specific manner

Inability to fully suppress sterol synthesis rates with exogenous sterol in embryonic and extraembyronic fetal tissues

Juxtamembranous aspartic acid in Insig-1 and Insig-2 is required for cholesterol homeostasis

Contact Info

Product

Resources

About