Genetics of Nonalcoholic Fatty Liver Disease: From Pathogenesis to Therapeutics

Sookoian, Silvia; Pirola, Carlos José

doi:10.1055/s-0039-1679920

Cited by 57 publications

(69 citation statements)

References 122 publications

(158 reference statements)

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“…Non-alcoholic fatty liver disease (NAFLD) represents a major burden on health systems around the world, as it has become the most prevalent chronic liver disease 1. The NAFLD natural history is modulated by genetic and environmental factors,2 including the gut microbiota that can explain a fraction of the disease heritability 2 3. Ample body of evidence indicates that the magnitude and severity of obesity and type 2 diabetes play a significant role in the disease prognosis 2 4 5.…”

Section: Introductionmentioning

confidence: 99%

“…The NAFLD natural history is modulated by genetic and environmental factors,2 including the gut microbiota that can explain a fraction of the disease heritability 2 3. Ample body of evidence indicates that the magnitude and severity of obesity and type 2 diabetes play a significant role in the disease prognosis 2 4 5. In fact, NAFLD exhibits high degree of comorbidity with disorders of the metabolic syndrome and shares with them pathogenic mechanisms of disease, including a state of chronic systemic inflammation 6…”

Section: Introductionmentioning

confidence: 99%

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Intrahepatic bacterial metataxonomic signature in non-alcoholic fatty liver disease

Sookoian

Salatino

Castaño

et al. 2020

Gut

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ObjectiveWe aimed to characterise the liver tissue bacterial metataxonomic signature in two independent cohorts of patients with biopsy-proven non-alcoholic fatty liver disease (NAFLD) diagnosis, as differences in the host phenotypic features—from moderate to severe obesity—may be associated with significant changes in the microbial DNA profile.Design and methodsLiver tissue samples from 116 individuals, comprising of 47 NAFLD overweight or moderately obese patients, 50 NAFLD morbidly obese patients elected for bariatric surgery and 19 controls, were analysed using high-throughput 16S rRNA gene sequencing.ResultsLiver bacterial DNA profile significantly differs between morbidly obese and non-morbidly obese patients with NAFLD. Bacteroidetes (p=1.8e-18) and Firmicutes (p=0.0044) were over-represented in morbidly obese patients and Proteobacteria (p=5.2e-10)—specifically Gammaproteobacteria and Alphaproteobacteria, and Deinococcus-Thermus (p=0.00012)—were over-represented in the non-morbidly obese cohort. Cohort-specific analysis of liver microbial DNA signatures shows patterns linked to obesity. The imbalance in Proteobacteria (Alpha or Gamma) among non-morbidly obese patients, and Peptostreptococcaceae, Verrucomicrobia, Actinobacteria and Gamma Proteobacteria DNA among morbidly obese patients was associated with histological severity. Decreased amounts of bacterial DNA from the Lachnospiraceae family were associated with more severe histological features. Proteobacteria DNA was consistently associated with lobular and portal inflammation scores. Microbial DNA composition corresponded to predicted functional differences.ConclusionThis is the first comprehensive study showing that the liver tissue of NAFLD patients contains a diverse repertoire of bacterial DNA (up to 2.5×104 read counts). The liver metataxonomic signature may explain differences in the NAFLD pathogenic mechanisms as well as physiological functions of the host.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Intrahepatic bacterial metataxonomic signature in non-alcoholic fatty liver disease

Sookoian

Salatino

Castaño

et al. 2020

Gut

Self Cite

119

140

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“…updated October 2019) biomedical articles available in the Medline and PubMed query interface associated with the terms "nonalcoholic fatty liver disease", with an increase from 656 (2010) to 2330 (2016) articles more recently (http://cbdm-01.zdv.uni-mainz.de/~jfontain/cms).Consequently, the concept of designating single mechanisms and/or single genes/proteins in NAFLD (as discussed above) has now evolved into exploration of multiple causal interactions using systems biology approaches. NAFLD represents a spectrum of histologic phenotypes with marked interindividual variability, as well as overlap with metabolic syndrome, and pleiotropy with other diseases (obesity, type 2 diabetes) as well as with several types of cancer(50,87).…”

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confidence: 99%

Genetic Pathways in Nonalcoholic Fatty Liver Disease: Insights From Systems Biology

et al. 2020

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Nonalcoholic fatty liver disease (NAFLD) represents a burgeoning worldwide epidemic whose etiology reflects multiple interactions between environmental and genetic factors. Here, we review the major pathways and dominant genetic modifiers known to be relevant players in human NAFLD and which may determine key components of the heritability of distinctive disease traits including steatosis and fibrosis. In addition, we have employed general assumptions which are based on known genetic factors in NAFLD to build a systems biology prediction model that includes functional enrichment. This prediction model highlights additional complementary pathways that represent plausible intersecting signaling networks that we define here as an NAFLD‐Reactome. We review the evidence connecting variants in each of the major known genetic modifiers (variants in patatin‐like phospholipase domain containing 3, transmembrane 6 superfamily member 2, membrane‐bound O‐acyltransferase domain containing 7, glucokinase regulator, and hydroxysteroid 17‐beta dehydrogenase 13) to NAFLD and expand the associated underlying mechanisms using functional enrichment predictions, based on both preclinical and cell‐based experimental findings. These major candidate gene variants function in distinct pathways, including substrate delivery for de novo lipogenesis; mitochondrial energy use; lipid droplet assembly, lipolytic catabolism, and fatty acid compartmentalization; and very low‐density lipoprotein assembly and secretion. The NAFLD‐Reactome model expands these pathways and allows for hypothesis testing, as well as serving as a discovery platform for druggable targets across multiple pathways that promote NAFLD development and influence several progressive outcomes. In conclusion, we summarize the strengths and weaknesses of studies implicating selected variants in the pathophysiology of NAFLD and highlight opportunities for future clinical research and pharmacologic intervention, as well as the implications for clinical practice.

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“…There are interesting examples of this concept in the literature that are worth highlighting. For example, the association of PNPLA3 ‐rs738409 with the susceptibility to diverse liver‐related phenotypes has been extensively replicated . Nevertheless, it would appear that the rs738409 variant may also exhibit pleiotropic effects.…”

Section: Discussionmentioning

confidence: 99%

Review article: shared disease mechanisms between non‐alcoholic fatty liver disease and metabolic syndrome – translating knowledge from systems biology to the bedside

Sookoian

Pirola

2019

Aliment Pharmacol Ther

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Background: Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease worldwide. Characterised by abnormal fat accumulation in the liver, NAFLD presents high degree of comorbidity with disorders of the metabolic syndrome, including type 2 diabetes, obesity and cardiovascular disease. These comorbidities have strong negative impact on the natural course of NAFLD and vice versa, whereby the presence of NAFLD substantially modifies the course and prognosis of metabolic syndrome-associated diseases.Aim: To use systems biology strategies to interrogate disease mechanisms that are common to NAFLD and metabolic syndrome. Methods:We mapped shared gene/protein-disease interaction networks, we performed gene-disease enrichment analysis to assess pleiotropy, and we created a genedrug connectivity network. Results:We found that a shared network of genes/proteins is overrepresented by immune response-related pathways, post-translational modifications of nuclear receptors, and platelet-related processes, including activation and platelet signalling.Likewise, gene-based disease-enrichment analysis suggested underlying molecular effectors that are shared with major systemic disorders, including diverse autoimmune diseases, kidney, respiratory and nervous system disorders, cancer and infectious diseases. The shared list of genes/proteins was enriched in drug targets for anti-inflammatory therapy, drugs used to treat cardiovascular diseases, antimicrobial agents and phytochemicals, among many other approved pharmaceutical compounds. By leveraging on publicly available OMICs data, we were able to show that shared loci are not necessarily affected by reverse causality. Conclusion:We provide evidence indicating that NAFLD treatment, including severe histological traits, cannot be limited to the use of a single drug, as it rather requires a multi-target therapeutic approach.

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Genetics of Nonalcoholic Fatty Liver Disease: From Pathogenesis to Therapeutics

Cited by 57 publications

References 122 publications

Intrahepatic bacterial metataxonomic signature in non-alcoholic fatty liver disease

Intrahepatic bacterial metataxonomic signature in non-alcoholic fatty liver disease

Genetic Pathways in Nonalcoholic Fatty Liver Disease: Insights From Systems Biology

Review article: shared disease mechanisms between non‐alcoholic fatty liver disease and metabolic syndrome – translating knowledge from systems biology to the bedside

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