Recent insights on the role of cholesterol in non-alcoholic fatty liver disease

Abstract

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of hepatic histopathological changes ranging from non-inflammatory intracellular fat deposition to non-alcoholic steatohepatitis (NASH), which may progress into hepatic fibrosis, cirrhosis, or hepatocellular carcinoma. NAFLD hallmark is the excessive hepatic accumulation of neutral lipids that result from an imbalance between lipid availability and lipid removal. Recent data suggest that disturbed hepatic cholesterol homeostasis and liver free cholesterol (FC) accumulation are relevant to the pathogenesis of NAFLD/NASH. Hepatic FC accumulation in NAFLD results from alterations in intracellular cholesterol transport and from unbalanced cellular cholesterol homeostasis characterized by activation of cholesterol biosynthetic pathways, increased cholesterol de-esterification and attenuation of cholesterol export and bile acid synthesis pathways. FC accumulation leads to liver injury through the activation of intracellular signaling pathways in Kupffer cells (KCs), Stellate cells (HSCs) and hepatocytes. The activation of KCs and HSCs promotes inflammation and fibrogenesis. In addition, FC accumulation in liver mitochondria induces mitochondrial dysfunction, which results in increasing production of reactive oxygen species, and triggers the unfolded protein response in the endoplasmic reticulum (ER) causing ER stress and apoptosis. These events create a vicious circle that contributes to the maintenance of steatosis and promotes ongoing hepatocyte death and liver damage, which in turn may translate into disease progression. In the present review we summarize the current knowledge on dysregulated cholesterol homeostasis in NAFLD and examine the cellular mechanisms of hepatic FC toxicity and its contribution to ongoing liver injury in this disease. The therapeutic implications of this knowledge are also discussed.

Human liver epigenetic alterations in non-alcoholic steatohepatitis are related to insulin action

“…Among those, there was differential methylation at genes involved in cholesterol transport and inflammation (ARL4C, encoding ADP-ribosylation factor-like 4C), 21,22 glucose metabolism and epigenetics (HDAC9, encoding histone deacetylase 9), 23 liver inflammation and coronary artery disease (COL4A1, encoding collagen, type IV, a 1), 24,25 and liver fibrogenesis (SEMA3E, encoding class 1 semaphorin and ITGB4, encoding integrin b 4 subunit, which is a receptor for laminins). 26,27 These observations may reflect, at the epigenetic level, the presence of hepatic inflammation in NASH and the liver fibrosis contributing to the progression of the disease, 1 in addition to disturbances in cholesterol transport that may participate in NAFLD progression 28 and the increased risk of cardiovascular disease. 29 On the other hand, we found only one CpG site differently methylated in steatosis, mapped to ALKBH5, which encodes an enzyme that demethylates RNA.…”

Dicer1/miR-29/HMGCR axis contributes to hepatic free cholesterol accumulation in mouse non-alcoholic steatohepatitis

“…Emerging evidence suggests that hepatic FC is a major lipotoxic molecule critical in the development of experimental and human NAFLD. Therefore, it is essential to understand the molecular mechanisms of cholesterol accumulation involved in the progression of NAFLD [3,43] . In our study, FC accumulation in the Dicer1-KO mouse liver was most likely due to its increased synthesis, resulting from the increased expression levels of HMGCR.…”

Cholesterol metabolism in cholestatic liver disease and liver transplantation: From molecular mechanisms to clinical implications

“…We discuss difficulties in assessing cholesterol metabolism, and summarize the cholesterol metabolism disturbances seen in cholestatic liver disease and before and after LT. Cholesterol metabolism in the setting of non-alcoholic steatohepatitis was recently reviewed [16] , and is not discussed here.…”