How does hepatic lipid accumulation lead to lipotoxicity in non-alcoholic fatty liver disease?

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Abstract

Background

Non-alcoholic fatty liver disease (NAFLD), characterized as excess lipid accumulation in the liver which is not due to alcohol use, has emerged as one of the major health problems around the world. The dysregulated lipid metabolism creates a lipotoxic environment which promotes the development of NAFLD, especially the progression from simple steatosis (NAFL) to non-alcoholic steatohepatitis (NASH).

Purposeand Aim

This review focuses on the mechanisms of lipid accumulation in the liver, with an emphasis on the metabolic fate of free fatty acids (FFAs) in NAFLD and presents an update on the relevant cellular processes/mechanisms that are involved in lipotoxicity. The changes in the levels of various lipid species that result from the imbalance between lipolysis/lipid uptake/lipogenesis and lipid oxidation/secretion can cause organellar dysfunction, e.g. ER stress, mitochondrial dysfunction, lysosomal dysfunction, JNK activation, secretion of extracellular vesicles (EVs) and aggravate (or be exacerbated by) hypoxia which ultimately lead to cell death. The aim of this review is to provide an overview of how abnormal lipid metabolism leads to lipotoxicity and the cellular mechanisms of lipotoxicity in the context of NAFLD.

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Most cited references 116

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A new definition for metabolic associated fatty liver disease: an international expert consensus statement

Mohammed Eslam, Philip N. Newsome, Quentin M Anstee … (2020)

The exclusion of other chronic liver diseases including "excess" alcohol intake has until now been necessary to establish a diagnosis of metabolic dysfunction-associated fatty liver disease (MAFLD). However, given our current understanding of the pathogenesis of MAFLD and its rising prevalence, "positive criteria" to diagnose the disease are required. In this work, a panel of international experts from 22 countries propose a new definition for the diagnosis of MAFLD that is both comprehensive and simple, and is independent of other liver diseases. The criteria are based on evidence of hepatic steatosis, in addition to one of the following three criteria, namely overweight/obesity, presence of type 2 diabetes mellitus, or evidence of metabolic dysregulation. We propose that disease assessment and stratification of severity should extend beyond a simple dichotomous classification to steatohepatitis vs. non-steatohepatitis. The group also suggests a set of criteria to define MAFLD-associated cirrhosis and proposes a conceptual framework to consider other causes of fatty liver disease. Finally, we bring clarity to the distinction between diagnostic criteria and inclusion criteria for research studies and clinical trials. Reaching consensus on the criteria for MAFLD will help unify the terminology (e.g. for ICD-coding), enhance the legitimacy of clinical practice and clinical trials, improve clinical care and move the clinical and scientific field of liver research forward.

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Mechanisms of NAFLD development and therapeutic strategies

Mary Rinella, Arun Sanyal, Scott Friedman … (2018)

There has been a rise in the prevalence of nonalcoholic fatty liver disease (NAFLD), paralleling a worldwide increase in diabetes and metabolic syndrome. NAFLD, a continuum of liver abnormalities from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), has a variable course but can lead to cirrhosis and liver cancer. Here we review the pathogenic and clinical features of NAFLD, its major comorbidities, clinical progression and risk of complications and in vitro and animal models of NAFLD enabling refinement of therapeutic targets that can accelerate drug development. We also discuss evolving principles of clinical trial design to evaluate drug efficacy and the emerging targets for drug development that involve either single agents or combination therapies intended to arrest or reverse disease progression.

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Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up.

Mattias Ekstedt, Hannes Hagström, Patrik Nasr … (2015)

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the Western world, strongly associated with insulin resistance and the metabolic syndrome. Nonalcoholic steatohepatitis, i.e., fatty liver accompanied by necroinflammatory changes, is mostly defined by the NAFLD activity score (NAS). The aim of the current study was to determine disease-specific mortality in NAFLD, and evaluate the NAS and fibrosis stage as prognostic markers for overall and disease-specific mortality. In a cohort study, data from 229 well-characterized patients with biopsy-proven NAFLD were collected. Mean follow-up was 26.4 (±5.6, range 6-33) years. A reference population was obtained from the National Registry of Population, and information on time and cause of death were obtained from the Registry of Causes of Death. NAFLD patients had an increased mortality compared with the reference population (hazard ratio [HR] 1.29, confidence interval [CI] 1.04-1.59, P = 0.020), with increased risk of cardiovascular disease (HR 1.55, CI 1.11-2.15, P = 0.01), hepatocellular carcinoma (HR 6.55, CI 2.14-20.03, P = 0.001), infectious disease (HR 2.71, CI 1.02-7.26, P = 0.046), and cirrhosis (HR 3.2, CI 1.05-9.81, P = 0.041). Overall mortality was not increased in patients with NAS 5-8 and fibrosis stage 0-2 (HR 1.41, CI 0.97-2.06, P = 0.07), whereas patients with fibrosis stage 3-4, irrespective of NAS, had increased mortality (HR 3.3, CI 2.27-4.76, P < 0.001). NAFLD patients have increased risk of death, with a high risk of death from cardiovascular disease and liver-related disease. The NAS was not able to predict overall mortality, whereas fibrosis stage predicted both overall and disease-specific mortality. © 2014 by the American Association for the Study of Liver Diseases.

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Author and article information

Contributors

Yana Geng:

ORCID: http://orcid.org/0000-0003-1529-0875

y.geng@umcg.nl

Klaas Nico Faber: k.n.faber@umcg.nl

Vincent E. de Meijer: v.e.de.meijer@umcg.nl

Hans Blokzijl: h.blokzijl@umcg.nl

Han Moshage: a.j.moshage@umcg.nl

Journal

Journal ID (nlm-ta): Hepatol Int

Journal ID (iso-abbrev): Hepatol Int

Title: Hepatology International

Publisher: Springer India (New Delhi )

ISSN (Print): 1936-0533

ISSN (Electronic): 1936-0541

Publication date (Electronic): 6 February 2021

Publication date PMC-release: 6 February 2021

Publication date Collection: February 2021

Volume: 15

Issue: 1

Pages: 21-35

Affiliations

[1 ]Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands

[2 ]Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

[3 ]GRID grid.4494.d, ISNI 0000 0000 9558 4598, Department of Hepatopancreatobiliary Surgery and Liver Transplantation, , University of Groningen, University Medical Center Groningen, ; Groningen, The Netherlands

Author information

Yana Geng http://orcid.org/0000-0003-1529-0875

Article

Publisher ID: 10121

DOI: 10.1007/s12072-020-10121-2

PMC ID: 7886759

PubMed ID: 33548031

SO-VID: 7fcd9f55-75ad-4498-9716-a40237931c2d

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 3 July 2020

Date accepted : 10 December 2020

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100010890, Chinese Government Scholarship;

Award ID: 201506210062

Award Recipient : Yana Geng

Funded by: University of Groningen

Custom metadata

ScienceOpen disciplines: Gastroenterology & Hepatology

Keywords: nafld,nash,mafld,free fatty acids,lipotoxicity,lipid metabolism,cell death,er stress,mitochondrial dysfunction,jnk

Data availability:

ScienceOpen disciplines: Gastroenterology & Hepatology

Keywords: nafld, nash, mafld, free fatty acids, lipotoxicity, lipid metabolism, cell death, er stress, mitochondrial dysfunction, jnk

How does hepatic lipid accumulation lead to lipotoxicity in non-alcoholic fatty liver disease?

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Abstract

Background

Purposeand Aim

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Karger: Gastroenterology

Most cited references 116

A new definition for metabolic associated fatty liver disease: an international expert consensus statement

Mechanisms of NAFLD development and therapeutic strategies

Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up.

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