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World J Diabetes. Jun 15, 2017; 8(6): 230-234
Published online Jun 15, 2017. doi: 10.4239/wjd.v8.i6.230
Statins redux: A re-assessment of how statins lower plasma cholesterol
Rajendra Raghow
Rajendra Raghow, Department of Veterans Affairs Medical Center, Memphis, TN 38104, United States
Rajendra Raghow, Department of Pharmacology, University of Tennessee Health Science Center, Memphis, TN 38163, United States
Author contributions: Raghow R solely wrote this paper.
Conflict-of-interest statement: Raghow R declares that there is neither a conflict of interest with regard to the publication discussed in this FOV communication nor with respect to a commercial entity.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Rajendra Raghow, PhD, Professor, Department of Veterans Affairs Medical Center, 1030 Jefferson Avenue, Memphis, TN 38104, United States. rraghow@uthsc.edu
Telephone: +1-901-5238990 Fax: +1-901-5237274
Received: October 26, 2016
Peer-review started: October 31, 2016
First decision: December 1, 2016
Revised: February 7, 2017
Accepted: April 23, 2017
Article in press: April 24, 2017
Published online: June 15, 2017
Processing time: 231 Days and 3.9 Hours
Abstract

Obesity associated dyslipidemia and its negative effects on the heart and blood vessels have emerged as a major healthcare challenge around the globe. The use of statins, potent inhibitors of hydroxyl-methyl glutaryl (HMG) Co-A reductase, a rate-limiting enzyme in cholesterol biosynthesis, has significantly reduced the rates of cardiovascular and general mortality in patients with coronary artery disease. How statins lower plasma cholesterol levels presents a mechanistic conundrum since persistent exposure to these drugs in vitro or in vivo is known to induce overexpression of the HMG Co-A reductase gene and protein. In an attempt to solve this mechanistic puzzle, Schonewille et al, studied detailed metabolic parameters of cholesterol synthesis, inter-organ flux and excretion in mice treated with 3 common statins, rosuvastatin, atorvastatin or lovastatin, each with its unique pharmacokinetics. From the measurements of the rates of heavy water (D2O) and [13C]-acetate incorporation into lipids, the authors calculated the rates of whole body and organ-specific cholesterol synthesis in control and statin-treated mice. These analyses revealed dramatic enhancement in the rates of hepatic cholesterol biosynthesis in statin-treated mice that concomitantly elicited lower levels of cholesterol in their plasma. The authors have provided strong evidence to indicate that statin treatment in mice led to induction of compensatory metabolic pathways that apparently mitigated an excessive accumulation of cholesterol in the body. It was noted however that changes in cholesterol metabolism induced by 3 statins were not identical. While sustained delivery of all 3 statins led to enhanced rates of biliary excretion of cholesterol and its fecal elimination, only atorvastatin treated mice elicited enhanced trans-intestinal cholesterol excretion. Thus, blockade of HMGCR by statins in mice was associated with profound metabolic adaptations that reset their cholesterol homeostasis. The findings of Schonewille et al, deserve to be corroborated and extended in patients in order to more effectively utilize these important cholesterol-lowering drugs in the clinic.

Keywords: Statins; Atorvastatin; Lovastatin; Rosuvastatin; Cholesterol synthesis; Hydroxyl-methyl glutaryl-CoA reductase

Core tip: Schonewille et al, comprehensively studied cholesterol metabolism (de-novo synthesis of cholesterol and its inter-organ flux, and fecal elimination) in mice treated with rosuvastatin, atorvastatin or lovastatin. These analyses revealed that the rates of whole body and organ-specific cholesterol synthesis were boosted by all three statins. Mice treated with statins also elicited enhanced rates of biliary excretion of cholesterol and its fecal elimination. Remarkably, the process of trans-intestinal cholesterol excretion was augmented by only atorvastatin. These data shed mechanistic light on how statin treatment led to organ-specific metabolic adaptations in mice to reset their cholesterol homeostasis.