Cellular and Molecular Mechanisms of NAFLD and HCC

Dear Colleagues,

This Special Issue focuses on a metabolic disease termed non-alcoholic fatty liver disease (NAFLD), a chronic condition that overlaps with both type 2 diabetes (T2D) and cardiovascular disease, two common manifestations of the metabolic syndrome. NAFLD is commonly viewed as the hepatic manifestation of the metabolic syndrome and encompasses a spectrum of disease states ranging from non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH, with different extent of fibrosis) to cirrhosis. As a chronic disease, NAFLD usually progresses from NAFL to NASH with increasing fibrosis and eventually cirrhosis. NAFLD is reversible up until NASH with extensive fibrosis. After that, the outcome is either hepatic decompensation that necessitates a liver transplant or hepatocellular carcinoma (HCC). As with the metabolic syndrome, the prevalence of NAFLD is high, in about 25% in the general population, and with a marked mortality risk that grows with increased fibrosis. Importantly, NAFLD is a hidden disease, i.e., it remains asymptomatic until it has reached severe liver impairment, and, with respect to liver inflammation and fibrosis, NAFLD has overtaken both alcoholic and virus-induced steatohepatitis. A common thread in the pathology of NAFLD is sustained cellular stress caused by a number of reasons and, when sustained, drives the disease toward a terminal state or HCC. In NAFL, such cellular stress results in dysregulated de novo lipogeneis and subsequent triglyceride sythesis, the latter deposited, at the cellular level, in cytoplasmic organelles termed lipid droplets. As NAFLD is part of the metabolic syndrome, dysregulation in hormonal control of white adipose tissue (WAT) results in the excess release of free fatty acids that, in return, contributes to both increased hepatic lipid accumulation as well as ER stress, the latter mainly released WAT-deerived palmitate. This early state, NAFL, intersects with T2D by, for example, recuiting key factors such as CHREBP and MLX to lipid droplets, rendering hepatocytes less capable of metabolizing glucose. Similarly, increased hepatic fat accumulation results in elevated sustained levels of circulating triglycerides (e.g., VLDL) that contribute directly to cardiovascular disease development. The resulting sequela of NAFLD is therefore often severe, impacting multiple metabolic systems in our body. We have for this issue compiled expert reviews that combine clinical aspects of NAFLD with pathology, model systems, and cellular mechanisms relevant to disease progression. Also included are expert reviews on the molecular mechanisms that feeds into the development of HCC as well as current developments in non-invasive diagnostics, recommended treatment, and surgical strategies for NAFLD, hepatic decompensation, and HCC.

Dr. Tommy Nilsson
Dr. Peter Metrakos
Dr. Anthoula Lazaris
Guest Editors

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• NAFLD
• HCC
• imaging
• ER stress
• pathology
• lipid droplets