Role of Cholesterol‐Associated Steatohepatitis in the Development of NASH

Abstract

The rising prevalence of nonalcoholic fatty liver disease (NAFLD) and NAFLD-related cirrhosis in the United States and globally highlights the need to better understand the mechanisms causing progression of hepatic steatosis to fibrosing steatohepatitis and cirrhosis in a small proportion of patients with NAFLD. Accumulating evidence suggests that lipotoxicity mediated by hepatic free cholesterol (FC) overload is a mechanistic driver for necroinflammation and fibrosis, characteristic of nonalcoholic steatohepatitis (NASH), in many animal models and also in some patients with NASH. Diet, lifestyle, obesity, key genetic polymorphisms, and hyperinsulinemia secondary to insulin resistance are pivotal drivers leading to aberrant cholesterol signaling, which leads to accumulation of FC within hepatocytes. FC overload in hepatocytes can lead to ER stress, mitochondrial dysfunction, development of toxic oxysterols, and cholesterol crystallization in lipid droplets, which in turn lead to hepatocyte apoptosis, necrosis, or pyroptosis. Activation of Kupffer cells and hepatic stellate cells by hepatocyte signaling and cholesterol loading contributes to this inflammation and leads to hepatic fibrosis. Cholesterol accumulation in hepatocytes can be readily prevented or reversed by statins. Observational studies suggest that use of statins in NASH not only decreases the substantially increased cardiovascular risk, but may ameliorate liver pathology. Conclusion: Hepatic FC loading may result in cholesterol-associated steatohepatitis and play an important role in the development and progression of NASH. Statins appear to provide significant benefit in preventing progression to NASH and NASH-cirrhosis. Randomized controlled trials are needed to demonstrate whether statins or statin/ezetimibe combination can effectively reverse steatohepatitis and liver fibrosis in patients with NASH. (Hepatology Communications 2021;0:1-24).

Pcsk9 Deletion Promotes Murine Nonalcoholic Steatohepatitis and Hepatic Carcinogenesis: Role of Cholesterol

“…Excess hepatic cholesterol has been shown to promote NASH in a variety of animal models, ( 14 , 16 , 21 , 28 , 29 ) through mechanisms involving endoplasmic reticulum (ER) stress, mitochondrial dysfunction, development of toxic oxysterols, or stabilization of the transcription factor TAZ. ( 30 ) We also demonstrated that in murine models of NASH driven by high‐fat, high‐cholesterol diets, excess cholesterol crystallizes in hepatocyte lipid droplets, and these cholesterol crystals might promote necroinflammation in NASH. ( 14 , 15 , 16 , 17 ) Here we also demonstrate increased hepatic free cholesterol and cholesterol crystallization in the Pcsk9 KO mice on 0.75% dietary cholesterol together with formation of “crown‐like structures” of CD68‐positive macrophages that surround and process hepatocytes and lipid droplets with cholesterol crystals (Fig.…”

Hepatic Mitochondrial Dysfunction and Risk of Liver Disease in an Ovine Model of “PCOS Males”

“…PLIN5 promotes lipid storage [ 69 ], and it is also increased in human steatosis [ 70 ]. Triglycerides mainly represent a “safe” storage for FA [ 50 ], whereas the accumulation of other lipotoxic lipids, such as cholesterol, FA, diacylglycerol, and ceramides, leads to cellular dysfunction [ 71 , 72 ]. Cholesterol accumulates in the liver when the total sum of the pathways involved in cholesterol synthesis and uptake exceeds the pathways involved in cholesterol removal [ 71 ].…”

IL-19 Contributes to the Development of Nonalcoholic Steatohepatitis by Altering Lipid Metabolism

“…The data supporting this possibility is supported by in vitro results. The pathophysiology of NASH is very complex and many cell types within the liver are involved at multiple levels [ 34 ]. In whole liver, the factors measured by QPCR were IL-6, TNF-α, and TGF-β.…”