Environment, Endocrine Disruptors, and Fatty Liver Disease Associated with Metabolic Dysfunction (MASLD)

Mosca, Antonella; Manco, Melania; Braghini, Maria Rita; Cianfarani, Stefano; Maggiore, Giuseppe; Alisi, Anna; Vania, Andrea

doi:10.3390/metabo14010071

Cited by 5 publications

(1 citation statement)

References 89 publications

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“…and certain lifestyle factors like a diet rich in saturated fats and refined carbohydrates, lack of physical activity, or alcohol consumption [ 49 ]. Additionally, there is a genetic predisposition influenced by environmental exposure to endocrine-disrupting chemicals (EDCs), which could help explain the differences found among different geographical areas [ 66 , 67 ]. On the contrary, coffee consumption may be associated with a lower risk of developing MASLD and hepatic fibrosis [ 68 ].…”

Section: Discussionmentioning

confidence: 99%

Prognostic Impact of Metabolic Syndrome and Steatotic Liver Disease in Hepatocellular Carcinoma Using Machine Learning Techniques

Gil-Rojas,

Suárez,

Martínez-Blanco

et al. 2024

Metabolites

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Metabolic dysfunction-associated steatotic liver disease (MASLD) currently represents the predominant cause of chronic liver disease and is closely linked to a significant increase in the risk of hepatocellular carcinoma (HCC), even in the absence of liver cirrhosis. In this retrospective multicenter study, machine learning (ML) methods were employed to investigate the relationship between metabolic profile and prognosis at diagnosis in a total of 219 HCC patients. The eXtreme Gradient Boosting (XGB) method demonstrated superiority in identifying mortality predictors in our patients. Etiology was the most determining prognostic factor followed by Barcelona Clinic Liver Cancer (BCLC) and Eastern Cooperative Oncology Group (ECOG) classifications. Variables related to the development of hepatic steatosis and metabolic syndrome, such as elevated levels of alkaline phosphatase (ALP), uric acid, obesity, alcohol consumption, and high blood pressure (HBP), had a significant impact on mortality prediction. This study underscores the importance of metabolic syndrome as a determining factor in the progression of HCC secondary to MASLD. The use of ML techniques provides an effective tool to improve risk stratification and individualized therapeutic management in these patients.

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Section: Discussionmentioning

confidence: 99%

Prognostic Impact of Metabolic Syndrome and Steatotic Liver Disease in Hepatocellular Carcinoma Using Machine Learning Techniques

Gil-Rojas,

Suárez,

Martínez-Blanco

et al. 2024

Metabolites

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Steatotic liver disease induced by TCPOBOP-activated hepatic constitutive androstane receptor: primary and secondary gene responses with links to disease progression

Sonkar,

Ma,

Waxman

2024

Toxicological Sciences

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Constitutive Androstane Receptor (CAR, Nr1i3), a liver nuclear receptor and xenobiotic sensor, induces drug, steroid and lipid metabolizing enzymes, stimulates liver hypertrophy and hyperplasia, and ultimately, hepatocellular carcinogenesis. The mechanisms linking early CAR responses to later disease development are poorly understood. Here we show that exposure of CD-1 mice to TCPOBOP, a halogenated xenochemical and selective CAR agonist ligand, induces pericentral steatosis marked by hepatic accumulation of cholesterol and neutral lipid, and elevated circulating alanine aminotransferase, indicating hepatocyte damage. TCPOBOP-induced steatosis was weaker in the pericentral region but stronger in the periportal region in females compared to males. Early (1-day) TCPOBOP transcriptional responses were enriched for CAR-bound primary response genes, and for lipogenesis and xenobiotic metabolism and oxidative stress protection pathways; late (2-wk) TCPOBOP responses included many CAR binding-independent secondary response genes, with enrichment for macrophage activation, immune response and cytokine and reactive oxygen species production. Late upstream regulators specific to TCPOBOP-exposed male liver were linked to pro-inflammatory responses and hepatocellular carcinoma progression. TCPOBOP administered weekly to male mice using a high corn oil vehicle activated carbohydrate-responsive transcription factor (MLXIPL)-regulated target genes, dysregulated mitochondrial respiratory and translation regulatory pathways, and induced more advanced liver pathology. Overall, TCPOBOP exposure recapitulates histological and gene expression changes characteristic of emerging steatotic liver disease, including secondary gene responses in liver non-parenchymal cells indicative of transition to a more advanced disease state. Upstream regulators of both the early and late TCPOBOP response genes include novel biomarkers for foreign chemical-induced metabolic dysfunction-associated steatotic liver disease.

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Steatotic liver disease induced by TCPOBOP-activated hepatic constitutive androstane receptor: Primary and secondary gene responses with links to disease progression

Sonkar,

Ma,

Waxman

2024

Preprint

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Constitutive Androstane Receptor (CAR,Nr1i3), a liver nuclear receptor and xenobiotic sensor, induces drug, steroid and lipid metabolizing enzymes, stimulates liver hypertrophy and hyperplasia, and ultimately, hepatocellular carcinogenesis. The mechanisms linking early CAR responses to subsequent disease development are poorly understood. Here we show that exposure of CD-1 mice to TCPOBOP, a halogenated xenochemical and selective CAR agonist ligand, induces pericentral steatosis marked by hepatic accumulation of cholesterol and neutral lipid, and elevated circulating alanine aminotransferase levels, indicating hepatocyte damage. TCPOBOP-induced steatosis was weaker in the pericentral region but stronger in the periportal region in females compared to males. Early (1-day) TCPOBOP transcriptional responses were enriched for CAR-bound primary response genes, and for lipid and xenobiotic metabolism and oxidative stress protection pathways; late (2-wk) TCPOBOP responses included many CAR binding-independent secondary response genes, with enrichment for immune response, macrophage activation, and cytokine and reactive oxygen species production. Late upstream regulators specific to TCPOBOP-exposed male liver were linked to pro-inflammatory responses and hepatocellular carcinoma progression. TCPOBOP administered weekly to male mice using a high corn oil vehicle activated carbohydrate-responsive transcription factor (MLXIPL)-regulated target genes, dysregulated mitochondrial respiratory and translation regulatory pathways, and induced more advanced liver pathology. Thus, TCPOBOP exposure recapitulates histological and gene expression changes characteristic of emerging steatotic liver disease, including secondary expression changes in liver non-parenchymal cells indicative of transition to a more advanced disease state. Upstream regulators of both the early and late TCPOBOP gene responses include novel biomarkers for foreign chemical-induced metabolic dysfunction-associated steatotic liver disease.

show abstract

Environment, Endocrine Disruptors, and Fatty Liver Disease Associated with Metabolic Dysfunction (MASLD)

Cited by 5 publications

References 89 publications

Prognostic Impact of Metabolic Syndrome and Steatotic Liver Disease in Hepatocellular Carcinoma Using Machine Learning Techniques

Prognostic Impact of Metabolic Syndrome and Steatotic Liver Disease in Hepatocellular Carcinoma Using Machine Learning Techniques

Steatotic liver disease induced by TCPOBOP-activated hepatic constitutive androstane receptor: primary and secondary gene responses with links to disease progression

Steatotic liver disease induced by TCPOBOP-activated hepatic constitutive androstane receptor: Primary and secondary gene responses with links to disease progression

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