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Pathogenesis of NASH: How Metabolic Complications of Overnutrition Favour Lipotoxicity and Pro-Inflammatory Fatty Liver Disease.
Adv Exp Med Biol. 2018; 1061:19-44.AE

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.

Authors+Show Affiliations

Australian National University Medical School, and Gastroenterology and Hepatology Unit, The Canberra Hospital, Woden, ACT, Australia. geoff.farrell@anu.edu.au.Australian National University Medical School, and Gastroenterology and Hepatology Unit, The Canberra Hospital, Woden, ACT, Australia.Australian National University Medical School, and Gastroenterology and Hepatology Unit, The Canberra Hospital, Woden, ACT, Australia.

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

29956204

Citation

Farrell, Geoffrey C., et al. "Pathogenesis of NASH: How Metabolic Complications of Overnutrition Favour Lipotoxicity and Pro-Inflammatory Fatty Liver Disease." Advances in Experimental Medicine and Biology, vol. 1061, 2018, pp. 19-44.
Farrell GC, Haczeyni F, Chitturi S. Pathogenesis of NASH: How Metabolic Complications of Overnutrition Favour Lipotoxicity and Pro-Inflammatory Fatty Liver Disease. Adv Exp Med Biol. 2018;1061:19-44.
Farrell, G. C., Haczeyni, F., & Chitturi, S. (2018). Pathogenesis of NASH: How Metabolic Complications of Overnutrition Favour Lipotoxicity and Pro-Inflammatory Fatty Liver Disease. Advances in Experimental Medicine and Biology, 1061, 19-44. https://doi.org/10.1007/978-981-10-8684-7_3
Farrell GC, Haczeyni F, Chitturi S. Pathogenesis of NASH: How Metabolic Complications of Overnutrition Favour Lipotoxicity and Pro-Inflammatory Fatty Liver Disease. Adv Exp Med Biol. 2018;1061:19-44. PubMed PMID: 29956204.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pathogenesis of NASH: How Metabolic Complications of Overnutrition Favour Lipotoxicity and Pro-Inflammatory Fatty Liver Disease. AU - Farrell,Geoffrey C, AU - Haczeyni,Fahrettin, AU - Chitturi,Shivakumar, PY - 2018/6/30/entrez PY - 2018/6/30/pubmed PY - 2018/11/18/medline KW - Inflammation KW - Lipotoxicity KW - Nonalcoholic fatty liver disease KW - Overnutrition SP - 19 EP - 44 JF - Advances in experimental medicine and biology JO - Adv Exp Med Biol VL - 1061 N2 - 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. SN - 0065-2598 UR - https://www.unboundmedicine.com/medline/citation/29956204/Pathogenesis_of_NASH:_How_Metabolic_Complications_of_Overnutrition_Favour_Lipotoxicity_and_Pro_Inflammatory_Fatty_Liver_Disease_ L2 - https://dx.doi.org/10.1007/978-981-10-8684-7_3 DB - PRIME DP - Unbound Medicine ER -