Free cholesterol accumulation in hepatic stellate cells: Mechanism of liver fibrosis aggravation in nonalcoholic steatohepatitis in mice

Abstract

These characteristic mechanisms of FC accumulation in HSCs are potential targets to treat liver fibrosis in liver diseases including NASH.

Ezetimibe in the balance: can cholesterol-lowering drugs alone be an effective therapy for NAFLD?

“…This implies that, when we analyse the effect of treatment as a dichotomous variable (improvement vs no improvement in fibrosis), there is no significant difference between arms (4/16 patients with improved fibrosis stage following ezetimibe compared with 1/12 in controls, p=0.136 with χ 2 test). While the impact on liver fibrosis needs further confirmation in larger studies, given the small number of patients included, the findings of this trial corroborate recent results from experimental models, suggesting that hepatic accumulation of non-triacylglycerol toxic lipid species (non-esterified cholesterol, saturated fatty acids, ceramides and diacylglycerols) triggers endoplasmic reticulum stress, mitochondrial dysfunction and oxidative stress, promoting liver injury, steatohepatitis and fibrosis [5,[7][8][9][10]. Several putative mechanisms linking cholesterol accumulation to hepatic stellate cell (HSC) activation and fibrogenesis have been demonstrated experimentally and reviewed elsewhere [5], including enhanced toll-like receptor (TLR)-4 pathway activation, which sensitises HSCs to the key fibrogenic factor transforming growth factor (TGF)-β1 [10], and reduces AMP-activated protein kinase-α (AMPK) activation [11] ( Fig.…”

Elevated free cholesterol in a p62 overexpression model of non-alcoholic steatohepatitis

“…Recent observations also highlighted the accumulation of free cholesterol as an important trigger for the progression from simple steatosis to severe NASH [9][10][11] . In fact, dietary cholesterol was demonstrated to be a critical factor in the progression of NASH [10,12] . Cholesterol fed to LDLR -/-mice induced a prominent inflammatory response, whereas high fat feeding without cholesterol induced steatosis in the absence of inflammation [13] .…”

The role of iNOS in cholesterol-induced liver fibrosis

“…Recently, attention has been given to the role of hepatic cholesterol content in NASH pathology. [6][7][8][9][10] Evidence collected from both human and animal models of NASH point to cholesterol as a potential mediator of lipotoxicity in NASH, including the development of hepatic fibrosis. In the first National Health and Nutrition Examination Survey in the United States, dietary cholesterol consumption was positively associated with the risk of cirrhosis or liver cancer.…”

“…Consistent with these findings, cholesterol-lowering agents, such as statins and ezetimibe, were shown to improve liver fibrosis among patients with hypercholesterolemia and mice with NASH. [8][9][10][11] Enhanced liver fibrosis is also evident in experimental studies conducted in rodents and rabbits following the consumption of a highcholesterol diet (HCD) containing cholic acid or a high-fat/ HCD diet or methionine-choline-deficient diet supplemented with cholesterol. 8,9 Initiation of chronic liver diseases commonly involves an inflammatory phase, which progresses to fibrosis after continuous oxidative stress.…”