Pathogenesis of NASH: How Metabolic Complications of Overnutrition Favour Lipotoxicity and Pro-Inflammatory Fatty Liver Disease

Abstract

Overnutrition, usually with obesity and genetic predisposition, lead to insulin resistance, which is an invariable accompaniment of nonalcoholic fatty liver disease (NAFLD). The associated metabolic abnormalities, pre- or established diabetes, hypertension and atherogenic dyslipidemia (clustered as metabolic syndrome) tend to be worse for nonalcoholic steatohepatitis (NASH), revealing it as part of a continuum of metabolic pathogenesis. The origins of hepatocellular injury and lobular inflammation which distinguish NASH from simple steatosis have intrigued investigators, but it is now widely accepted that NASH results from liver lipotoxicity. The key issue is not the quantity of liver fat but the type(s) of lipid molecules that accumulate, and how they are "packaged" to avoid subcellular injury. Possible lipotoxic mediators include free (unesterified) cholesterol, saturated free fatty acids, diacylglycerols, lysophosphatidyl-choline, sphingolipids and ceramide. Lipid droplets are intracellular storage organelles for non-structural lipid whose regulation is influenced by genetic polymorphisms, such as PNPLA3. Cells unable to sequester chemically reactive lipid molecules undergo mitochondrial injury, endoplasmic reticulum (ER) stress and autophagy, all processes of interest for NASH pathogenesis. Lipotoxicity kills hepatocytes by apoptosis, a highly regulated, non-inflammatory form of cell death, but also by necrosis, necroptosis and pyroptosis; the latter involve mitochondrial injury, oxidative stress, activation of c-Jun N-terminal kinase (JNK) and release of danger-associated molecular patterns (DAMPs). DAMPs stimulate innate immunity by binding pattern recognition receptors, such as Toll-like receptor 4 (TLR4) and the NOD-like receptor protein 3 (NLRP3) inflammasome, which release a cascade of pro-inflammatory chemokines and cytokines. Thus, lipotoxic hepatocellular injury attracts inflammatory cells, particularly activated macrophages which surround ballooned hepatocytes as crown-like structures. In both experimental and human NASH, livers contain cholesterol crystals which are a second signal for NLRP3 activation; this causes interleukin (IL)-1β and IL18 secretion to attract and activate macrophages and neutrophils. Injured hepatocytes also liberate plasma membrane-derived extracellular vesicles; these have been shown to circulate in NASH and to be pro-inflammatory. The way metabolic dysfunction leads to lipotoxicity, innate immune responses and the resultant pattern of cellular inflammation in the liver are likely also relevant to hepatic fibrogenesis and hepatocarcinogenesis. Pinpointing the key molecules involved pharmacologically should eventually lead to effective pharmacotherapy against NASH.

SCO‐792, an enteropeptidase inhibitor, improves disease status of diabetes and obesity in mice

“…Considering the pivotal role of insulin signaling in the maintenance of muscle mass, 28 weight, which increased abnormally in ob/ob mice, decreased upon treatment with SCO-792. As it is widely accepted that liver lipotoxicity induces nonalcoholic steatohepatitis, 30 SCO-792-treatment may also offer benefits for this condition.…”

Autocrine IL11 cis-signaling in hepatocytes is an initiating nexus between lipotoxicity and non-alcoholic steatohepatitis

“…2D). The production of reactive oxygen species (ROS) from damaged mitochondria is important for lipotoxicity [22] and ROS from NOX4 is also pertinent in NASH [28]. We found that X209 prevented ROS production in sFA-loaded hepatocytes and that this was accompanied by partial restoration of glutathione (GSH) levels ( Fig.…”

“…The factors underlying the transition from non-alcoholic fatty liver disease (NAFLD) to NASH are multifactorial but lipid loading of hepatocytes is of central importance [21]. Certain lipid species are toxic for hepatocytes and lipotoxicity leads to cytokine release causing hepatocyte death along with activation of hepatic stellate cells (HSCs) and immune cells [21,22]. Lipotoxicity, such as that due to palmitate [23], is an early event in NASH and represents a linkage between diet, NAFLD and NASH.…”

Necroptotic Cell Death in Liver Transplantation and Underlying Diseases: Mechanisms and Clinical Perspective

“…Nonalcoholic fatty liver disease (NAFLD) is a common pathological condition associated with obesity, diabetes, and metabolic syndrome, resulting in fat accumulation in the liver without the history of alcohol abuse. NAFLD can develop into nonalcoholic steatohepatitis (NASH), where fat accumulation triggers inflammation (hepatitis) . NAFLD/NASH is currently the most rapidly expanding indication for liver transplantation in developed countries.…”

“…NAFLD can develop into nonalcoholic steatohepatitis (NASH), where fat accumulation triggers inflammation (hepatitis). (43) NAFLD/NASH is currently the most rapidly expanding indication for liver transplantation in developed countries. Progressive steatohepatitis is associated with extensive apoptosis in hepatocytes induced by free fatty acids.…”