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Oxidative Medicine and Cellular Longevity
Volume 2018, Article ID 2548154, 15 pages
https://doi.org/10.1155/2018/2548154
Review Article

Hypoxic Signaling and Cholesterol Lipotoxicity in Fatty Liver Disease Progression

Institute of Biochemistry, Food Science and Nutrition, The R.H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel

Correspondence should be addressed to Oren Tirosh; li.ca.ijuh.liam@hsorit.nero

Received 25 February 2018; Revised 30 April 2018; Accepted 14 May 2018; Published 31 May 2018

Academic Editor: Anna M. Giudetti

Copyright © 2018 Oren Tirosh. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Cholesterol is the only lipid whose absorption in the gastrointestinal tract is limited by gate-keeping transporters and efflux mechanisms, preventing its rapid absorption and accumulation in the liver and blood vessels. In this review, I explored the current data regarding cholesterol accumulation in liver cells and key mechanisms in cholesterol-induced fatty liver disease associated with the activation of deleterious hypoxic and nitric oxide signal transduction pathways. Although nonalcoholic fatty liver disease (NAFLD) affects both obese and nonobese individuals, the mechanism of NAFLD progression in lean individuals with healthy metabolism is puzzling. Lean NAFLD individuals exhibit normal metabolic responses, implying that liver damage is not associated with impaired metabolism per se and that direct lipotoxic effects are crucial for disease progression. Several redox and oxidant signaling pathways involving cholesterol are at play in fatty liver disease development. These include impairment of the mitochondrial and lysosomal function by cholesterol loading of the inner-cell membranes; formation of cholesterol crystals and hepatocyte degradation; and crown-like structures surrounding degrading hepatocytes, activating Kupffer cells, and evoking inflammation. The current review focuses on the induction of liver inflammation, fibrosis, and steatosis by free cholesterol via the hypoxia-inducible factor 1α (HIF-1α), a main oxygen-sensing transcription factor involved in all stages of NAFLD. Cholesterol loading in hepatocytes can result in chronic HIF-1α activity because of the decreased oxygen availability and excessive production of nitric oxide and mitochondrial reactive oxygen species.