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Altered Lipid Moieties and Carbonyls in a Wistar Rat Dietary Model of Subclinical Fatty Liver: Potential Sex-Specific Biomarkers of Early Fatty Liver Disease?

ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is a condition in which excess fat builds up in the liver. To date, there is a lack of knowledge about the subtype of lipid structures affected in the early stages of NAFLD. The aim of this study was to analyze serum and liver lipid moieties, specifically unsaturations and carbonyls, by nuclear magnetic resonance (NMR) in a subclinical Wistar rat model of NAFLD for detecting early alterations and potential sex dimorphisms. Twelve weeks of a high-fat diet (HFD) induced fat accumulation in the liver to a similar extent in male and female Wistar rats. In addition to total liver fat accumulation, Wistar rats showed a shift in lipid subtype composition. HFD rats displayed increased lipid carbonyls in both liver and serum, and decreased in unsaturated fatty acids (UFAs) and polyunsaturated fatty acids (PUFAs), with a much stronger effect in male than female animals. Our results revealed that the change in fat was not only quantitative but also qualitative, with dramatic shifts in relevant lipid structures. Finally, we compared the results found in Wistar rats with an analysis in a human patient cohort of extreme obesity. For the first time to our knowledge, lipid carbonyl levels and lipoproteins profiles were analyzed in the context of subclinical NAFLD. The association found between lipid carbonyls and alanine aminotransferase (ALT) in a human cohort of extremely obese individuals further supports the potential role of lipid moieties as biomarkers of early NAFLD.

SUBMITTER: Martin-Grau M

PROVIDER: S-EPMC10604774 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Altered Lipid Moieties and Carbonyls in a Wistar Rat Dietary Model of Subclinical Fatty Liver: Potential Sex-Specific Biomarkers of Early Fatty Liver Disease?

Martín-Grau María M Pardo-Tendero Mercedes M Casanova Pilar P Dromant Mar M Marrachelli Vannina G VG Morales Jose Manuel JM Borrás Consuelo C Pisoni Serena S Maestrini Sabrina S Di Blasio Anna M AM Monleon Daniel D

Antioxidants (Basel, Switzerland) 20230928 10

Non-alcoholic fatty liver disease (NAFLD) is a condition in which excess fat builds up in the liver. To date, there is a lack of knowledge about the subtype of lipid structures affected in the early stages of NAFLD. The aim of this study was to analyze serum and liver lipid moieties, specifically unsaturations and carbonyls, by nuclear magnetic resonance (NMR) in a subclinical Wistar rat model of NAFLD for detecting early alterations and potential sex dimorphisms. Twelve weeks of a high-fat diet ...[more]

PMID: 37891887

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Project description:Nonalcoholic fatty liver disease (NAFLD), largely studied as a condition of overnutrition, also presents in undernourished populations. Like NAFLD, undernutrition disrupts systemic metabolism and has been linked to gut microbiota dysbiosis. Indeed, chronic exposures to fecal microbes contribute to undernutrition pathology in regions with poor sanitation. Despite a growing prevalence of fatty liver disease, the influence of undernutrition and the gut microbiota remain largely unexplored. Here, we utilize an established murine model (C57BL/6J mice placed on a malnourished diet that received iterative Escherichia coli/Bacteroidales gavage [MBG mice]) that combines a protein/fat-deficient diet and iterative exposure to specific, fecal microbes. Fecal-oral contamination exacerbates triglyceride accumulation in undernourished mice. MBG livers exhibit diffuse lipidosis accompanied by striking shifts in fatty acid, glycerophospholipid, and retinol metabolism. Multiomic analyses revealed metabolomic pathways linked to the undernourished gut microbiome and hepatic steatosis, including phenylacetate metabolism. Intriguingly, fatty liver features were observed only in the early-life, but not adult, MBG model despite similar liver metabolomic profiles. Importantly, we demonstrate that dietary intervention largely mitigates aberrant metabolomic and microbiome features in MBG mice. These findings indicate a crucial window in early-life development that, when disrupted by nutritional deficiency, may significantly influence liver function. Our work provides a multifaceted study of how diet and gut microbes inform fatty liver progression and reversal during undernutrition.IMPORTANCE Nonalcoholic fatty liver disease (NAFLD) remains a global epidemic, but it is often studied in the context of obesity and aging. Nutritional deficits, however, also trigger hepatic steatosis, influencing health trajectories in undernourished pediatric populations. Here, we report that exposure to specific gut microbes impacts fatty liver pathology in mice fed a protein/fat-deficient diet. We utilize a multiomics approach to (i) characterize NAFLD in the context of early undernutrition and (ii) examine the impact of diet and gut microbes in the pathology and reversal of hepatic steatosis. We provide compelling evidence that an early-life, critical development window facilitates undernutrition-induced fatty liver pathology. Moreover, we demonstrate that sustained dietary intervention largely reverses fatty liver features and microbiome shifts observed during early-life malnutrition.

Project description:Obesity increases the risk for cardiomyopathy in the absence of comorbidities. Myocardial structure is modified by dietary fatty acids. Left ventricular hypertrophy is associated with Western (WES) diet consumption, whereas intake of n-3 polyunsaturated fatty acids is associated with antihypertrophic effects. We previously observed no attenuation of left ventricular thickening after 3 months of docosahexaenoic acid (DHA) supplementation of a WES diet, compared with WES diet intake alone, in rats that had similar weight, adiposity, and insulin sensitivity to control animals. The objective of this study was to define left ventricular gene expression in these animals to determine whether diet alone was associated with a physiologic or pathologic hypertrophic response. We hypothesized that WES diet consumption would favor a pathologic or maladaptive myocardial gene expression pattern and that DHA supplementation would favor a physiologic or adaptive response. Microarray analysis identified 64 transcripts that were differentially expressed (P ≤ .001) within one or more treatment comparisons. Using quantitative real-time polymerase chain reaction, 29 genes with fold change at least 1.74 were successfully validated; all but 3 had similar directionality to that observed using microarray, and 2 genes, connective tissue growth factor and cathepsin M, were differentially expressed according to diet. WES blot analysis was performed on 4 proteins relevant to myocardial hypertrophy and metabolism. Acyl-CoA thioesterase 1, B-cell translocation gene 2, and carbonic anhydrase III showed directional change consistent with gene expression. Retinol saturase (all-trans-retinol 13,14-reductase), although not consistent with gene expression, was different according to diet, with increased concentrations in WES-fed rats compared with control and DHA-supplemented animals. Diet did not distinguish a transcriptome reflecting physiologic or pathologic myocardial hypertrophy; furthermore, the modest changes observed suggest that obesity and associated comorbidities may play a larger role than mere dietary fatty acid composition in development of cardiomyopathy.

Dataset Information

Altered Lipid Moieties and Carbonyls in a Wistar Rat Dietary Model of Subclinical Fatty Liver: Potential Sex-Specific Biomarkers of Early Fatty Liver Disease?

Publications

Altered Lipid Moieties and Carbonyls in a Wistar Rat Dietary Model of Subclinical Fatty Liver: Potential Sex-Specific Biomarkers of Early Fatty Liver Disease?

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