The pathogenesis of non-alcoholic fatty liver disease (NAFLD) is associated with abnormalities of liver lipid metabolism. On the contrary, a diet enriched with n-3 polyunsaturated fatty acids (n-3-PUFAs) has been reported to ameliorate the progression of NAFLD. The aim of our study was to investigate the impact of dietary n-3-PUFA enrichment on the development of NAFLD and liver lipidome. Mice were fed for 6 weeks either a high-fat methionine choline-deficient diet (MCD) or standard chow with or without n-3-PUFAs. Liver histology, serum biochemistry, detailed plasma and liver lipidomic analyses, and genome-wide transcriptome analysis were performed. Mice fed an MCD developed histopathological changes characteristic of NAFLD, and these changes were ameliorated with n-3-PUFAs. Simultaneously, n-3-PUFAs decreased serum triacylglycerol and cholesterol concentrations as well as ALT and AST activities. N-3-PUFAs decreased serum concentrations of saturated and monounsaturated free fatty acids (FAs), while increasing serum concentrations of long-chain PUFAs. Furthermore, in the liver, the MCD significantly increased the hepatic triacylglycerol content, while the administration of n-3-PUFAs eliminated this effect. Administration of n-3-PUFAs led to significant beneficial differences in gene expression within biosynthetic pathways of cholesterol, FAs, and pro-inflammatory cytokines (IL-1 and TNF-α). To conclude, n-3-PUFA supplementation appears to represent a promising nutraceutical approach for the restoration of abnormalities in liver lipid metabolism and the prevention and treatment of NAFLD.

• Klíčová slova
• lipidome, lipids, n-3 fatty acids, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis,
• MeSH
• cholesterol metabolismus   MeSH
• cholin metabolismus   MeSH
• dieta s vysokým obsahem tuků škodlivé účinky   MeSH
• játra metabolismus   MeSH
• kyseliny mastné neesterifikované metabolismus   MeSH
• methionin metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nealkoholová steatóza jater * etiologie   genetika   MeSH
• nenasycené mastné kyseliny metabolismus   MeSH
• omega-3 mastné kyseliny * farmakologie   terapeutické užití   metabolismus   MeSH
• Racemethionin metabolismus   farmakologie   MeSH
• triglyceridy metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cholesterol MeSH
• cholin MeSH
• kyseliny mastné neesterifikované MeSH
• methionin MeSH
• nenasycené mastné kyseliny MeSH
• omega-3 mastné kyseliny * MeSH
• Racemethionin MeSH
• triglyceridy MeSH

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disorder worldwide. The aim of our study was to assess the role of bilirubin, and the heme oxygenase 1 (HMOX1) and bilirubin UDP-glucuronosyl transferase (UGT1A1) promoter gene variants, which are involved in bilirubin homeostasis, in the NAFLD development in adult patients. The study was performed on 84 patients with NAFLD and 103 age/sex-matched controls. Routine biochemistry, inflammatory markers, adipokines, and the fibrosis/steatohepatitis stage were determined in the NAFLD patients. The (GT)n/(TA)n dinucleotide variations in HMOX1/UGT1A1 gene promoters, respectively, were analyzed by fragment analysis. Compared to controls, serum bilirubin concentrations in NAFLD patients tended to be decreased, while the prevalence of phenotypic Gilbert syndrome was significantly low. Genetic variations in HMOX1 and UGT1A1 gene promoters did not differ between NAFLD patients and controls, and no relationship was found in the NAFLD patients between these gene variants and any of the laboratory or histological parameters. In conclusion, metabolism of bilirubin is dysregulated in NAFLD patients, most likely due to increased oxidative stress, since frequencies of the major functional variants in the HMOX1 or UGT1A1 gene promoters did not have any effect on development of NAFLD in adult patients.

• Klíčová slova
• HMOX1, NAFLD, NASH, UGT1A1, bilirubin, bilirubin UDP-glucuronosyl transferase, heme oxygenase 1, oxidative stress,
• Publikační typ
• časopisecké články MeSH

Nonalcoholic fatty liver disease (NAFLD) is a growing concern worldwide, affecting 25% of the global population. NAFLD is a multifactorial disease with a broad spectrum of pathology includes steatosis, which gradually progresses to a more severe condition such as nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and eventually leads to hepatic cancer. Several risk factors, including exposure to environmental toxicants, are involved in the development and progression of NAFLD. Environmental factors may promote the development and progression of NAFLD by various biological alterations, including mitochondrial dysfunction, reactive oxygen species production, nuclear receptors dysregulation, and interference in inflammatory and immune-mediated signaling. Moreover, environmental contaminants can influence immune responses by impairing the immune system's components and, ultimately, disease susceptibility. Flame retardants (FRs) are anthropogenic chemicals or mixtures that are being used to inhibit or delay the spread of fire. FRs have been employed in several household and outdoor products; therefore, human exposure is unavoidable. In this review, we summarized the potential mechanisms of FRs-associated immune and inflammatory signaling and their possible contribution to the development and progression of NAFLD, with an emphasis on FRs-mediated interferon signaling. Knowledge gaps are identified, and emerging pharmacotherapeutic molecules targeting the immune and inflammatory signaling for NAFLD are also discussed.

• Klíčová slova
• cytokines, flame retardants, interferon, metabolic disruption, metabolism-disrupting chemicals, nonalcoholic fatty liver disease,
• MeSH
• biologické markery MeSH
• cílená molekulární terapie MeSH
• cytokiny metabolismus   MeSH
• interferony metabolismus   MeSH
• játra účinky léků   metabolismus   patologie   MeSH
• lidé MeSH
• mediátory zánětu metabolismus   MeSH
• náchylnost k nemoci * MeSH
• nealkoholová steatóza jater etiologie   metabolismus   patologie   MeSH
• objevování léků MeSH
• retardanty hoření škodlivé účinky   MeSH
• signální transdukce * MeSH
• zánět etiologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• biologické markery MeSH
• cytokiny MeSH
• interferony MeSH
• mediátory zánětu MeSH
• retardanty hoření MeSH

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the Western world, and it persists at a high prevalence. NAFLD is characterised by the accumulation of triglycerides in the liver and includes a spectrum of histopathological findings, ranging from simple fatty liver through non-alcoholic steatohepatitis (NASH) to fibrosis and ultimately cirrhosis, which may progress to hepatocellular carcinoma. The pathogenesis of NAFLD is closely related to the metabolic syndrome and insulin resistance. Understanding the pathophysiology and treatment of NAFLD in humans has currently been limited by the lack of satisfactory animal models. The ideal animal model for NAFLD should reflect all aspects of the intricate etiopathogenesis of human NAFLD and the typical histological findings of its different stages. Within the past several years, great emphasis has been placed on the development of an appropriate model for human NASH. This paper reviews the widely used experimental models of NAFLD in rats. We discuss nutritional, genetic and combined models of NAFLD and their pros and cons. The choice of a suitable animal model for this disease while respecting its limitations may help to improve the understanding of its complex pathogenesis and to discover appropriate therapeutic strategies. Considering the legislative, ethical, economical and health factors of NAFLD, animal models are essential tools for the research of this disease.

• Klíčová slova
• Animal model, High-fat diet, Methionine- and choline-deficient diet, Non-alcoholic fatty liver disease, Non-alcoholic steatohepatitis, Otsuka-Long-Evans-Tokushima fatty rats, Zucker rats,
• MeSH
• druhová specificita MeSH
• fenotyp MeSH
• genetická predispozice k nemoci MeSH
• jaterní cirhóza metabolismus   patologie   patofyziologie   MeSH
• játra metabolismus   patologie   patofyziologie   MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• modely nemocí na zvířatech * MeSH
• nealkoholová steatóza jater * etiologie   genetika   metabolismus   patologie   patofyziologie   MeSH
• nutriční stav MeSH
• progrese nemoci MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The temporal relationship of hepatic steatosis and changes in liver oxidative stress and fatty acid (FA) composition to the development of non-alcoholic steatohepatitis (NASH) remain to be clearly defined. Recently, we developed an experimental model of hepatic steatosis and NASH, the transgenic spontaneously hypertensive rat (SHR) that overexpresses a dominant positive form of the human SREBP-1a isoform in the liver. These rats are genetically predisposed to hepatic steatosis at a young age that ultimately progresses to NASH in older animals. Young transgenic SHR versus SHR controls exhibited simple hepatic steatosis which was associated with significantly increased hepatic levels of oxidative stress markers, conjugated dienes, and TBARS, with decreased levels of antioxidative enzymes and glutathione and lower concentrations of plasma alpha- and gamma-tocopherol. Transgenic rats exhibited increased plasma levels of saturated FA, decreased levels of n-3 and n-6 polyunsaturated FA (PUFA), and increased n-6/n-3 PUFA ratios. These results are consistent with the hypothesis that excess fat accumulation in the liver in association with increased oxidative stress and disturbances in the metabolism of saturated and unsaturated fatty acids may precede and contribute to the primary pathogenesis of NASH.

• MeSH
• genetická predispozice k nemoci MeSH
• játra metabolismus   patologie   MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• nenasycené mastné kyseliny metabolismus   MeSH
• oxidační stres * MeSH
• potkani inbrední SHR MeSH
• potkani transgenní MeSH
• protein SREBP1 genetika   metabolismus   MeSH
• ztučnělá játra genetika   metabolismus   patologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• nenasycené mastné kyseliny MeSH
• protein SREBP1 MeSH
• SREBF1 protein, human MeSH Prohlížeč