Statins increase hepatic cholesterol synthesis and stimulate fecal cholesterol elimination in mice

Schonewille, Marleen; Boer, Jan Freark de; Mele, Laura; Wolters, Henk; Bloks, Vincent W.; Wolters, Justina C.; Kuivenhoven, Jan Albert; Tietge, Uwe J. F.; Brufau, Gemma; Groen, Albert K.

doi:10.1194/jlr.m067488

Cited by 117 publications

(104 citation statements)

References 57 publications

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“…3 B ). Short-term treatment with statins in mice did not result in a reduction of total cholesterol levels (data not shown), which is in agreement with previous reports (25). Similarly, in murine primary hepatocytes, increasing doses of atorvastatin did not affect cellular miR-122 levels ( P trend =0.575), but markedly reduced miR-122 in the culture medium ( P trend <0.001; Fig.…”

Section: Resultssupporting

confidence: 93%

Circulating MicroRNA-122 Is Associated With the Risk of New-Onset Metabolic Syndrome and Type 2 Diabetes

et al. 2016

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MicroRNA-122 (miR-122) is abundant in the liver and involved in lipid homeostasis, but its relevance to the long-term risk of developing metabolic disorders is unknown. We therefore measured circulating miR-122 in the prospective population-based Bruneck Study (n = 810; survey year 1995). Circulating miR-122 was associated with prevalent insulin resistance, obesity, metabolic syndrome, type 2 diabetes, and an adverse lipid profile. Among 92 plasma proteins and 135 lipid subspecies quantified with mass spectrometry, it correlated inversely with zinc-α-2-glycoprotein and positively with afamin, complement factor H, VLDL-associated apolipoproteins, and lipid subspecies containing monounsaturated and saturated fatty acids. Proteomics analysis of livers from antagomiR-122–treated mice revealed novel regulators of hepatic lipid metabolism that are responsive to miR-122 inhibition. In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT, n = 155), 12-month atorvastatin reduced circulating miR-122. A similar response to atorvastatin was observed in mice and cultured murine hepatocytes. Over up to 15 years of follow-up in the Bruneck Study, multivariable adjusted risk ratios per one-SD higher log miR-122 were 1.60 (95% CI 1.30–1.96; P < 0.001) for metabolic syndrome and 1.37 (1.03–1.82; P = 0.021) for type 2 diabetes. In conclusion, circulating miR-122 is strongly associated with the risk of developing metabolic syndrome and type 2 diabetes in the general population.

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Section: Resultssupporting

confidence: 93%

Circulating MicroRNA-122 Is Associated With the Risk of New-Onset Metabolic Syndrome and Type 2 Diabetes

et al. 2016

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“…However, statins block synthesis of sterol and nonsterol isoprenoids that mediate feedback regulation of reductase. This results in a marked accumulation of reductase (up to 200-fold) in livers of animals and humans (13,40,41) that allows for continued synthesis of cholesterol and thereby blunts cholesterol-lowering effects of statins (42)(43)(44)(45). The statin-induced accumulation of hepatic reductase is blunted (5-fold) in knockin mice harboring mutations that prevent sterol-induced ubiquitination of reductase compared to their wild type counterparts (46).…”

Section: Discussionmentioning

confidence: 99%

Schnyder corneal dystrophy-associated UBIAD1 is defective in MK-4 synthesis and resists autophagy-mediated degradation

Jun

Schumacher

Hwang

et al. 2020

Journal of Lipid Research

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The autosomal dominant disorder Schnyder corneal dystrophy (SCD) is caused by mutations in UbiA prenyltransferase domain-containing protein-1 (UBIAD1), which uses geranylgeranyl pyrophosphate (GGpp) to synthesize the vitamin K2 subtype menaquinone-4 (MK-4). SCD is characterized by opacification of the cornea, owing to aberrant build-up of cholesterol in the tissue. We previously discovered that sterols stimulate association of UBIAD1 with endoplasmic reticulum (ER)-localized HMG CoA reductase, which catalyzes a rate-limiting step in synthesis of cholesterol and nonsterol isoprenoids, including GGpp. Binding to UBIAD1 inhibits sterol-accelerated, ER-associated degradation (ERAD) of reductase and permits continued synthesis of GGpp in cholesterol-replete cells. GGpp disrupts UBIAD1-reductase binding and thereby allows for maximal ERAD of reductase as well as ER-to-Golgi translocation of UBIAD1. SCD-associated UBIAD1 is refractory to GGpp-mediated dissocation from reductase and remains sequestered in ER to inhibit ERAD. Here, we report development of a biochemical assay for UBIAD1-mediated synthesis of MK-4 in isolated membranes and intact cells. Using this assay, we compared enzymatic activity of wild type UBIAD1 with that of SCD-associated variants. Our studies revealed that SCDassociated UBIAD1 exhibited reduced MK-4 synthetic activity, which may result from their reduced affinity for GGpp. Sequestration in the ER protects SCD-associated UBIAD1 from autophagy and allows intracellular accumulation of the mutant protein, which amplifies the inhibitory effect on reductase ERAD. These findings have important implications not only for the understanding of SCD etiology, but also for the efficacy of cholesterollowering statin therapy, which becomes limited in part because of UBIAD1-mediated inhibition of reductase ERAD. Keywords: endoplasmic reticulum/Golgi apparatus/vesicular transport/menaquinone-4/autophagy/cholesterolby guest, on July 4, 2020 www.jlr.org Downloaded from

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“…The general idea is that statins reduce and EZE increases DNCS, although the DNCS reducing effect of statins has recently been questioned [6]. As in our original studies [1, 2, 4], the daily chol synthesis rate (mg/d) is generally determined applying the cholesterol balance approach measuring the daily dietary chol input rate and the daily fecal excretion rate of chol metabolites and bile acids [7].…”

Section: Model Establishmentmentioning

confidence: 99%

The Interpretation of Cholesterol Balance Derived Synthesis Data and Surrogate Noncholesterol Plasma Markers for Cholesterol Synthesis under Lipid Lowering Therapies

Stellaard¹,

Lütjohann²

2017

Cholesterol

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The cholesterol balance procedure allows the calculation of cholesterol synthesis based on the assumption that loss of endogenous cholesterol via fecal excretion and bile acid synthesis is compensated by de novo synthesis. Under ezetimibe therapy hepatic cholesterol is diminished which can be compensated by hepatic de novo synthesis and hepatic extraction of plasma cholesterol. The plasma lathosterol concentration corrected for total cholesterol concentration (R_Lath) as a marker of de novo cholesterol synthesis is increased during ezetimibe treatment but unchanged under treatment with ezetimibe and simvastatin. Cholesterol balance derived synthesis data increase during both therapies. We hypothesize the following. (1) The cholesterol balance data must be applied to the hepatobiliary cholesterol pool. (2) The calculated cholesterol synthesis value is the sum of hepatic de novo synthesis and the net plasma—liver cholesterol exchange rate. (3) The reduced rate of biliary cholesterol absorption is the major trigger for the regulation of hepatic cholesterol metabolism under ezetimibe treatment. Supportive experimental and literature data are presented that describe changes of cholesterol fluxes under ezetimibe, statin, and combined treatments in omnivores and vegans, link plasma R_Lath to liver function, and define hepatic de novo synthesis as target for regulation of synthesis. An ezetimibe dependent direct hepatic drug effect cannot be excluded.

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Statins increase hepatic cholesterol synthesis and stimulate fecal cholesterol elimination in mice

Cited by 117 publications

References 57 publications

Circulating MicroRNA-122 Is Associated With the Risk of New-Onset Metabolic Syndrome and Type 2 Diabetes

Circulating MicroRNA-122 Is Associated With the Risk of New-Onset Metabolic Syndrome and Type 2 Diabetes

Schnyder corneal dystrophy-associated UBIAD1 is defective in MK-4 synthesis and resists autophagy-mediated degradation

The Interpretation of Cholesterol Balance Derived Synthesis Data and Surrogate Noncholesterol Plasma Markers for Cholesterol Synthesis under Lipid Lowering Therapies

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