Metabolic drivers of non-alcoholic fatty liver disease
Background: The incidence of non-alcoholic fatty liver disease (NAFLD) is rapidly increasing worldwide parallel to the global obesity epidemic. NAFLD encompasses a range of liver pathologies and most often originates from metabolically driven accumulation of fat in the liver, or non-alcoholic fatty...
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doaj-7677ba72ae8b4601ba5bd33defb080382021-07-23T04:48:47ZengElsevierMolecular Metabolism2212-87782021-08-0150101143Metabolic drivers of non-alcoholic fatty liver diseaseKendra K. Bence0Morris J. Birnbaum1Corresponding author. Pfizer, Inc., Internal Medicine Research Unit, 1 Portland Street, 4th floor, Cambridge, MA, 02139, USA.; Internal Medicine Research Unit, Pfizer Worldwide Research, Development, and Medical, Cambridge, MA, USAInternal Medicine Research Unit, Pfizer Worldwide Research, Development, and Medical, Cambridge, MA, USABackground: The incidence of non-alcoholic fatty liver disease (NAFLD) is rapidly increasing worldwide parallel to the global obesity epidemic. NAFLD encompasses a range of liver pathologies and most often originates from metabolically driven accumulation of fat in the liver, or non-alcoholic fatty liver (NAFL). In a subset of NAFL patients, the disease can progress to non-alcoholic steatohepatitis (NASH), which is a more severe form of liver disease characterized by hepatocyte injury, inflammation, and fibrosis. Significant progress has been made over the past decade in our understanding of NASH pathogenesis, but gaps remain in our mechanistic knowledge of the precise metabolic triggers for disease worsening. Scope of review: The transition from NAFL to NASH likely involves a complex constellation of multiple factors intrinsic and extrinsic to the liver. This review focuses on early metabolic events in the establishment of NAFL and initial stages of NASH. We discuss the association of NAFL with obesity as well as the role of adipose tissue in disease progression and highlight early metabolic drivers implicated in the pathological transition from hepatic fat accumulation to steatohepatitis. Major conclusions: The close association of NAFL with features of metabolic syndrome highlight plausible mechanistic roles for adipose tissue health and the release of lipotoxic lipids, hepatic de novo lipogenesis (DNL), and disruption of the intestinal barrier in not only the initial establishment of hepatic steatosis, but also in mediating disease progression. Human genetic variants linked to NASH risk to date are heavily biased toward genes involved in the regulation of lipid metabolism, providing compelling support for the hypothesis that NASH is fundamentally a metabolic disease.http://www.sciencedirect.com/science/article/pii/S2212877820302179NAFLDNASHObesityAdipose tissueLipotoxicityFructose |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Kendra K. Bence Morris J. Birnbaum |
spellingShingle |
Kendra K. Bence Morris J. Birnbaum Metabolic drivers of non-alcoholic fatty liver disease Molecular Metabolism NAFLD NASH Obesity Adipose tissue Lipotoxicity Fructose |
author_facet |
Kendra K. Bence Morris J. Birnbaum |
author_sort |
Kendra K. Bence |
title |
Metabolic drivers of non-alcoholic fatty liver disease |
title_short |
Metabolic drivers of non-alcoholic fatty liver disease |
title_full |
Metabolic drivers of non-alcoholic fatty liver disease |
title_fullStr |
Metabolic drivers of non-alcoholic fatty liver disease |
title_full_unstemmed |
Metabolic drivers of non-alcoholic fatty liver disease |
title_sort |
metabolic drivers of non-alcoholic fatty liver disease |
publisher |
Elsevier |
series |
Molecular Metabolism |
issn |
2212-8778 |
publishDate |
2021-08-01 |
description |
Background: The incidence of non-alcoholic fatty liver disease (NAFLD) is rapidly increasing worldwide parallel to the global obesity epidemic. NAFLD encompasses a range of liver pathologies and most often originates from metabolically driven accumulation of fat in the liver, or non-alcoholic fatty liver (NAFL). In a subset of NAFL patients, the disease can progress to non-alcoholic steatohepatitis (NASH), which is a more severe form of liver disease characterized by hepatocyte injury, inflammation, and fibrosis. Significant progress has been made over the past decade in our understanding of NASH pathogenesis, but gaps remain in our mechanistic knowledge of the precise metabolic triggers for disease worsening. Scope of review: The transition from NAFL to NASH likely involves a complex constellation of multiple factors intrinsic and extrinsic to the liver. This review focuses on early metabolic events in the establishment of NAFL and initial stages of NASH. We discuss the association of NAFL with obesity as well as the role of adipose tissue in disease progression and highlight early metabolic drivers implicated in the pathological transition from hepatic fat accumulation to steatohepatitis. Major conclusions: The close association of NAFL with features of metabolic syndrome highlight plausible mechanistic roles for adipose tissue health and the release of lipotoxic lipids, hepatic de novo lipogenesis (DNL), and disruption of the intestinal barrier in not only the initial establishment of hepatic steatosis, but also in mediating disease progression. Human genetic variants linked to NASH risk to date are heavily biased toward genes involved in the regulation of lipid metabolism, providing compelling support for the hypothesis that NASH is fundamentally a metabolic disease. |
topic |
NAFLD NASH Obesity Adipose tissue Lipotoxicity Fructose |
url |
http://www.sciencedirect.com/science/article/pii/S2212877820302179 |
work_keys_str_mv |
AT kendrakbence metabolicdriversofnonalcoholicfattyliverdisease AT morrisjbirnbaum metabolicdriversofnonalcoholicfattyliverdisease |
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