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Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: The central role of nontriglyceride fatty acid metabolites†
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A significant body of evidence now forces us to rethink the causes of NASH. Once thought to be a disease caused by triglyceride accumulation in hepatocytes with subsequent oxidant stress and lipid peroxidation causing inflammation and fibrosis, new data from animal studies and a limited number of human studies now provide convincing evidence that triglyceride accumulation does not cause insulin resistance or cellular injury in the liver. The lipotoxic liver injury hypothesis for the pathogenesis of NASH suggests that we need to focus our therapeutic efforts on reducing the burden of fatty acids going to the liver or being synthesized in the liver. This can be accomplished by improving insulin sensitivity at the level of adipose tissue to prevent inappropriate peripheral lipolysis and by preventing unnecessary de novo lipogenesis in the liver. Excess carbohydrates are the major substrates for de novo lipogenesis, and thus, reducing carbohydrate consumption through dietary changes and increasing muscle glucose uptake through exercise remain important cornerstones of treatment and prevention of lipotoxic liver injury, a disease hitherto called NASH.
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“NASH may therefore be grossly viewed as an influx problem due to increased fatty acid load with consecutive lipotoxicity,11 12”
From Novel therapeutic targets for cholestatic and fatty liver disease (2022) · cites this paper as [11]
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“Fatty acid (FA)-induced lipotoxicity results in cellular stress of hepatocytes,11 but also cholangiocytes25 and HSCs.26”
From Novel therapeutic targets for cholestatic and fatty liver disease (2022) · cites this paper as [11]
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The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD)
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Rinella, M. E., Neuschwander-Tetri, B. A., Siddiqui, M. S., Abdelmalek, M. F., Caldwell, S., Barb, D., Kleiner, D. E., & Loomba, R. (2023) · Hepatology · doi:10.1097/hep.0000000000000323 · Cited by 2,667
Self-citationChalasani, N., Younossi, Z. M., Lavine, J. E., Diehl, A. M., Brunt, E. M., Cusi, K. J., Charlton, M., & Sanyal, A. J. (2012) · Gastroenterology · doi:10.1053/j.gastro.2012.04.001 · Cited by 1,805
Metadata
- Authors
- Neuschwander‐Tetri, B. A.
- Affiliations
- Saint Louis University (US)
- Corresponding author
- Neuschwander‐Tetri, Brent A.
- Venue
- Hepatology
- Published
- 2010-08
- Volume
- 52
- Issue
- 2
- Pages
- 774-788
- ISSN
- 0270-9139 (ISSN-L)
- OpenAlex
- W2107943478
- Cited by
- 1,077
- References
- 196
- Citations by year
- 2026: 29 · 2025: 61 · 2024: 66 · 2023: 78 · 2022: 75 · 2021: 86 · 2020: 106 · 2019: 72 · 2018: 66 · 2017: 72 · 2016: 77 · 2015: 60 · 2014: 64 · 2013: 52 · 2012: 47
- FWCI
- 5.87
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Keywords
- nonalcoholic steatohepatitis, hepatic lipotoxicity, NASH pathogenesis, triglyceride accumulation, insulin resistance, de novo lipogenesis, adipose tissue insulin sensitivity, lipolysis, carbohydrate intake, physical activity, muscle glucose uptake
- MeSH terms
- Fatty Acids, Fatty Liver, Humans, Insulin Resistance, Liver, Causality, Oxidative Stress, Lipid Metabolism
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