Hypoxic Signaling and Cholesterol Lipotoxicity in Fatty Liver Disease Progression

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.

Diet-Induced Rat Model of Gradual Development of Non-Alcoholic Fatty Liver Disease (NAFLD) with Lipopolysaccharides (LPS) Secretion

“…Moreover, direct lipotoxicity of free fatty acids and other lipids increase the inflammation process, as well as cholesterol synthesis in the liver. Therefore, the dietary NAFLD model, associated with NASH development, contains cholesterol as one of the "hit" factors in the hypothesis of multiple-hits in NAFLD progression [21].…”

Impact of the Co-Administration of N-3 Fatty Acids and Olive Oil Components in Preclinical Nonalcoholic Fatty Liver Disease Models: A Mechanistic View

“…Nonalcoholic fatty liver disease (NAFLD) is considered the hepatic expression of the metabolic syndrome, which is characterized by (i) the accumulation of triacylglycerol (TG) in the cytoplasm of hepatocytes; (ii) a 25% prevalence in the population worldwide; (iii) the manifestation of a spectrum of liver alterations including simple hepatic steatosis, steatosis with inflammation (steatohepatitis, NASH), and different degrees of fibrosis; (iv) the absence of approved pharmacological therapies; and (v) the estimation that 20%-30% of NAFLD patients may progress to NASH [1]. The latter inflammatory condition is estimated to evolve to cirrhosis in 7%-25% of the patients [1,2] and represents an indication for liver transplantation with a consistently increasing frequency [3]. In this scenario, the diminution in the energy intake with concomitant physical activity is the first strategy for the adequate handling of NAFLD.…”

Xanthophyll β‐Cryptoxanthin Inhibits Highly Refined Carbohydrate Diet–Promoted Hepatocellular Carcinoma Progression in Mice

“…The tumor microenvironment is characterized by hypoxia that is thought to contribute to the development and progression of NAFLD‐driven HCC . Hepatic lipid accumulation has been reported to induce hypoxia in the hepatic microenvironment predisposing the liver to hepatic injuries and HCC .…”