In Vitro and In Vivo Models of Non-Alcoholic Fatty Liver Disease: A Critical Appraisal

Soret, Pierre‐Antoine; Magusto, Julie; Housset, Chantal; Gautheron, Jérémie

doi:10.3390/jcm10010036

Cited by 78 publications

(94 citation statements)

References 163 publications

(203 reference statements)

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“…To investigate the direct effects of butyrate on the liver, studies often use simple cell cultures such as HepG2 cells [28]. In MAFLD development and progression, communication between different cell types is essential [4,29].…”

Section: Introductionmentioning

confidence: 99%

The Effects of Butyrate on Induced Metabolic-Associated Fatty Liver Disease in Precision-Cut Liver Slices

et al. 2021

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Metabolic-associated fatty liver disease (MAFLD) starts with hepatic triglyceride accumulation (steatosis) and can progress to more severe stages such as non-alcoholic steatohepatitis (NASH) and even cirrhosis. Butyrate, and butyrate-producing bacteria, have been suggested to reduce liver steatosis directly and systemically by increasing liver β-oxidation. This study aimed to examine the influence of butyrate directly on the liver in an ex vivo induced MAFLD model. To maintain essential intercellular interactions, precision-cut liver slices (PCLSs) were used. These PCLSs were prepared from male C57BL/6J mice and cultured in varying concentrations of fructose, insulin, palmitic acid and oleic acid, to mimic metabolic syndrome. Dose-dependent triglyceride accumulation was measured after 24 and 48 h of incubation with the different medium compositions. PCLSs viability, as indicated by ATP content, was not affected by medium composition or the butyrate concentration used. Under induced steatotic conditions, butyrate did not prevent triglyceride accumulation. Moreover, it lowered the expression of genes encoding for fatty acid oxidation and only increased C4 related carnitines, which indicate butyrate oxidation. Nevertheless, butyrate lowered the fibrotic response of PCLSs, as shown by reduced gene expression of fibronectin, alpha-smooth muscle actin and osteopontin, and protein levels of type I collagen. These results suggest that in the liver, butyrate alone does not increase lipid β-oxidation directly but might aid in the prevention of MAFLD progression to NASH and cirrhosis.

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Section: Introductionmentioning

confidence: 99%

The Effects of Butyrate on Induced Metabolic-Associated Fatty Liver Disease in Precision-Cut Liver Slices

et al. 2021

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“…BOPTA accumulation in hepatocytes is modulated by the activity of these influx and efflux transporters. Experimental nonalcoholic fatty livers can be investigated in Zucker fatty (fa/fa) rats [7,8]. These rats have a mutated leptin receptor and a decreased leptin affinity.…”

Section: Introductionmentioning

confidence: 99%

Steatosis Alters the Activity of Hepatocyte Membrane Transporters in Obese Rats

Pastor

Vilgrain

2021

Cells

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Fat accumulation (steatosis) in ballooned hepatocytes alters the expression of membrane transporters in Zucker fatty (fa/fa) rats. The aim of the study was to quantify the functions of these transporters and their impact on hepatocyte concentrations using a clinical hepatobiliary contrast agent (Gadobenate dimeglumine, BOPTA) for liver imaging. In isolated and perfused rat livers, we quantified BOPTA accumulation and decay profiles in fa/+ (normal) and fa/fa hepatocytes by placing a gamma counter over livers. Profiles of BOPTA accumulation and decay in hepatocytes were analysed with nonlinear regressions to characterise BOPTA influx and efflux across hepatocyte transporters. At the end of the accumulation period, BOPTA hepatocyte concentrations and influx clearances were not significantly different in fa/+ and fa/fa livers. In contrast, bile clearance was significantly lower in fatty hepatocytes while efflux clearance back to sinusoids compensated the low efflux into canaliculi. The time when BOPTA cellular efflux impacts the accumulation profile of hepatocyte concentrations was slightly delayed (2 min) by steatosis, anticipating a delayed emptying of hepatocytes. The experimental model is useful for quantifying the functions of hepatocyte transporters in liver diseases.

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“…In addition, tissue-on-a-chip models have been developed and show great promise. Some advances in modelling NAFLD were recently reviewed by Soret et al [ 165 ].…”

Section: In Vitro Models For Examining the Role Of Cyp2e1 And Ffa On Liver Fibrosis And Damagementioning

confidence: 99%

CYP2E1 in Alcoholic and Non-Alcoholic Liver Injury. Roles of ROS, Reactive Intermediates and Lipid Overload

Harjumäki

Pridgeon

Ingelman‐Sundberg

2021

IJMS

114

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CYP2E1 is one of the fifty-seven cytochrome P450 genes in the human genome and is highly conserved. CYP2E1 is a unique P450 enzyme because its heme iron is constitutively in the high spin state, allowing direct reduction of, e.g., dioxygen, causing the formation of a variety of reactive oxygen species and reduction of xenobiotics to toxic products. The CYP2E1 enzyme has been the focus of scientific interest due to (i) its important endogenous function in liver homeostasis, (ii) its ability to activate procarcinogens and to convert certain drugs, e.g., paracetamol and anesthetics, to cytotoxic end products, (iii) its unique ability to effectively reduce dioxygen to radical species causing liver injury, (iv) its capability to reduce compounds, often generating radical intermediates of direct toxic or indirect immunotoxic properties and (v) its contribution to the development of alcoholic liver disease, steatosis and NASH. In this overview, we present the discovery of the enzyme and studies in humans, 3D liver systems and genetically modified mice to disclose its function and clinical relevance. Induction of the CYP2E1 enzyme either by alcohol or high-fat diet leads to increased severity of liver pathology and likelihood to develop ALD and NASH, with subsequent influence on the occurrence of hepatocellular cancer. Thus, fat-dependent induction of the enzyme might provide a link between steatosis and fibrosis in the liver. We conclude that CYP2E1 has many important physiological functions and is a key enzyme for hepatic carcinogenesis, drug toxicity and liver disease.

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In Vitro and In Vivo Models of Non-Alcoholic Fatty Liver Disease: A Critical Appraisal

Cited by 78 publications

References 163 publications

The Effects of Butyrate on Induced Metabolic-Associated Fatty Liver Disease in Precision-Cut Liver Slices

The Effects of Butyrate on Induced Metabolic-Associated Fatty Liver Disease in Precision-Cut Liver Slices

Steatosis Alters the Activity of Hepatocyte Membrane Transporters in Obese Rats

CYP2E1 in Alcoholic and Non-Alcoholic Liver Injury. Roles of ROS, Reactive Intermediates and Lipid Overload

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