Mechanisms and disease consequences of nonalcoholic fatty liver disease

Loomba, Rohit; Friedman, Scott L.; Shulman, Gerald I.

doi:10.1016/j.cell.2021.04.015

Cited by 856 publications

(555 citation statements)

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“…Here, we would like simply to recall some of the most relevant principles and concepts that have emerged in these years and then some of the most promising approaches. However, we have to immediately state that, at present, as very recently emphasized by Scott Friedman and coworkers, there are no drugs specifically approved to treat hepatic fibrosis for any human CLD, whatever the etiology [ 147 , 148 , 149 ]. Before briefly analyzing the current therapeutic approaches emerging from preclinical studies, one should take in mind that, whenever possible, the most effective strategy to affect CLD progression remains to eliminate the etiological agent or condition leading to chronic liver injury.…”

Section: Antifibrotic Therapies For Cld: a Synthetic Overviewmentioning

confidence: 99%

“…The most outstanding examples are represented by either the tremendous efficacy of direct antiviral agents (i.e., against HBV- and HCV-elated CLD) or by the long-term results obtained by abstinence from alcohol consumption. For all other CLDs, these options do not exists, and, as suggested by different authors, anti-fibrotic therapeutic strategies and therapeutic targets may be briefly analyzed according to the following critical options, as recently outlined particularly for progressive NAFLD [ 4 , 5 , 6 , 8 , 9 , 147 , 148 , 149 , 150 ].…”

Section: Antifibrotic Therapies For Cld: a Synthetic Overviewmentioning

confidence: 99%

“…Another promising approach emerged in recent years is represented by strategies targeting liver macrophages (either Kupffer cells or monocyte/macrophage from peripheral blood) as well as those signaling pathways underlying their recruitment and/or activation [ 12 , 13 , 149 , 153 ]. Pre-clinical studies have identified a number of critical targets for this anti-inflammatory purpose, including the CCR2/5 pathway, the serine/threonine apoptosis-stimulated kinase 1 (ASK1), several Toll-like receptors (TLR), galectin 3, Adenosine A3 receptor, vascular adhesion protein 1 (VAP-1) and others.…”

Section: Antifibrotic Therapies For Cld: a Synthetic Overviewmentioning

confidence: 99%

“…Pre-clinical studies have identified a number of critical targets for this anti-inflammatory purpose, including the CCR2/5 pathway, the serine/threonine apoptosis-stimulated kinase 1 (ASK1), several Toll-like receptors (TLR), galectin 3, Adenosine A3 receptor, vascular adhesion protein 1 (VAP-1) and others. Worthy of mention are at least four drugs: (i) Cenicriviroc, a double inhibitor of the CCR2/5 pathway that alone (NCT03028740) has entered into Phase III trials for NAFLD patients or it is under evaluation in combination with tropifexor, a potent farnesoid X receptor (FXR) agonist [ 149 ]; this drug is of potential interest since it can also target HSC/MFs and not only liver macrophages. (ii) Selonsertib, a selective inhibitor of ASK1, expected to block inflammation and fibrosis through necrosis and apoptosis, which was found to be ineffective in NASH patients with Stage 3 fibrosis and cirrhosis in two distinct Phase III trials (NCT03053063 and NCT03053050) [ 149 ].…”

Section: Antifibrotic Therapies For Cld: a Synthetic Overviewmentioning

confidence: 99%

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Hypoxia, Hypoxia-Inducible Factors and Liver Fibrosis

Foglia

Novo

Protopapa

et al. 2021

Cells

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Liver fibrosis is a potentially reversible pathophysiological event, leading to excess deposition of extracellular matrix (ECM) components and taking place as the net result of liver fibrogenesis, a dynamic and highly integrated process occurring during chronic liver injury of any etiology. Liver fibrogenesis and fibrosis, together with chronic inflammatory response, are primarily involved in the progression of chronic liver diseases (CLD). As is well known, a major role in fibrogenesis and fibrosis is played by activated myofibroblasts (MFs), as well as by macrophages and other hepatic cell populations involved in CLD progression. In the present review, we will focus the attention on the emerging pathogenic role of hypoxia, hypoxia-inducible factors (HIFs) and related mediators in the fibrogenic progression of CLD.

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Section: Antifibrotic Therapies For Cld: a Synthetic Overviewmentioning

confidence: 99%

Section: Antifibrotic Therapies For Cld: a Synthetic Overviewmentioning

confidence: 99%

Section: Antifibrotic Therapies For Cld: a Synthetic Overviewmentioning

confidence: 99%

Section: Antifibrotic Therapies For Cld: a Synthetic Overviewmentioning

confidence: 99%

See 2 more Smart Citations

Hypoxia, Hypoxia-Inducible Factors and Liver Fibrosis

Foglia

Novo

Protopapa

et al. 2021

Cells

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“…NAFLD has become the leading liver disease worldwide with an estimated 2 billion individuals affected [ 25 ]. NAFLD represents a spectrum of disease that may develop in individuals without significant alcohol consumption [ 26 ] and ranges from steatosis to steatohepatitis.…”

Section: General Aspects Of Nafldmentioning

confidence: 99%

Mitochondria Matter: Systemic Aspects of Nonalcoholic Fatty Liver Disease (NAFLD) and Diagnostic Assessment of Liver Function by Stable Isotope Dynamic Breath Tests

Ciaula

Calamita

Shanmugam

et al. 2021

IJMS

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The liver plays a key role in systemic metabolic processes, which include detoxification, synthesis, storage, and export of carbohydrates, lipids, and proteins. The raising trends of obesity and metabolic disorders worldwide is often associated with the nonalcoholic fatty liver disease (NAFLD), which has become the most frequent type of chronic liver disorder with risk of progression to cirrhosis and hepatocellular carcinoma. Liver mitochondria play a key role in degrading the pathways of carbohydrates, proteins, lipids, and xenobiotics, and to provide energy for the body cells. The morphological and functional integrity of mitochondria guarantee the proper functioning of β-oxidation of free fatty acids and of the tricarboxylic acid cycle. Evaluation of the liver in clinical medicine needs to be accurate in NAFLD patients and includes history, physical exam, imaging, and laboratory assays. Evaluation of mitochondrial function in chronic liver disease and NAFLD is now possible by novel diagnostic tools. “Dynamic” liver function tests include the breath test (BT) based on the use of substrates marked with the non-radioactive, naturally occurring stable isotope 13C. Hepatocellular metabolization of the substrate will generate 13CO2, which is excreted in breath and measured by mass spectrometry or infrared spectroscopy. Breath levels of 13CO2 are biomarkers of specific metabolic processes occurring in the hepatocyte cytosol, microsomes, and mitochondria. 13C-BTs explore distinct chronic liver diseases including simple liver steatosis, non-alcoholic steatohepatitis, liver fibrosis, cirrhosis, hepatocellular carcinoma, drug, and alcohol effects. In NAFLD, 13C-BT use substrates such as α-ketoisocaproic acid, methionine, and octanoic acid to assess mitochondrial oxidation capacity which can be impaired at an early stage of disease. 13C-BTs represent an indirect, cost-effective, and easy method to evaluate dynamic liver function. Further applications are expected in clinical medicine. In this review, we discuss the involvement of liver mitochondria in the progression of NAFLD, together with the role of 13C-BT in assessing mitochondrial function and its potential use in the prevention and management of NAFLD.

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New-Onset Age of Nonalcoholic Fatty Liver Disease and Cancer Risk

Liu,

Zhang

et al. 2023

JAMA Netw Open

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ImportanceThe onset age of nonalcoholic fatty liver disease (NAFLD) is decreasing, and whether earlier ages of NAFLD onset are associated with increased cancer risk is currently unclear.ObjectiveTo explore the association between NAFLD new-onset age and cancer risk.Design, Setting, and ParticipantsThis cohort study was conducted among 179 328 participants included in the Kailuan Cohort Study between 2006 and 2021. In total, 46 100 incident NAFLD cases were identified. For each case, a participant matched by age (older or younger by 1 year) and sex was randomly selected to create a new matched study cohort. Data were analyzed from December 2022 through April 2023.ExposureOnset of NAFLD.Main Outcomes and MeasuresThe association between the onset age of NAFLD and the risk of different cancer types was evaluated using weighted Cox regression models. Population-attributable fractions (PAFs) were used to quantify the association of NAFLD with cancer risk at different ages.ResultsAmong 63 696 participants (mean [SD] age, 51.37 [12.43] years; ‭10 932 females [17.2%] and ‭52 764 males [82.8%]), 31 848 individuals had NAFLD and 31 848 individuals were in the control group. During a median (IQR) follow-up of 10.16 (7.89-11.67) years, 2415 patients were diagnosed with cancer. Compared with the matched group, patients aged less than 45 years at NAFLD onset exhibited a higher risk of cancer (average hazard ratio [AHR], 1.52; 95% CI, 1.09-2.12), and as the onset age of NAFLD increased, the cancer risk decreased (ages 45-54 years: AHR, 1.50; 95% CI, 1.15-1.97; ages 55-64 years: AHR, 1.13; 95% CI, 0.97-1.33; ages &gt;65 years: AHR, 0.75; 95% CI, 0.45-1.27; P for interaction &lt; .001). Among patients aged less than 45 years at NAFLD onset, cancers were mainly digestive system and lung cancers, with AHR values of 2.00 (95% CI, 1.08-3.47) and 2.14 (95% CI, 1.05-4.36), respectively. PAFs also showed that in patients aged less than 45 years at NAFLD onset, 17.83% (95% CI, 4.92%-29.86%) of cancer risk was attributable to NAFLD.‬‬‬‬Conclusions and RelevanceThis study found that NAFLD was associated with increased cancer risk and there was an interaction with onset age, such that the younger the onset age of NAFLD, the greater the cancer risk.

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Mechanisms and disease consequences of nonalcoholic fatty liver disease

Cited by 856 publications

References 403 publications

Hypoxia, Hypoxia-Inducible Factors and Liver Fibrosis

Hypoxia, Hypoxia-Inducible Factors and Liver Fibrosis

Mitochondria Matter: Systemic Aspects of Nonalcoholic Fatty Liver Disease (NAFLD) and Diagnostic Assessment of Liver Function by Stable Isotope Dynamic Breath Tests

New-Onset Age of Nonalcoholic Fatty Liver Disease and Cancer Risk

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