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Study on the effects and mechanisms of alcohol combined with high-fat diet in promoting enteritis-induced liver injury

ABSTRACT: Inflammatory hepatic injury associated with inflammatory bowel disease (IBD) is a type of liver disease that occurs in patients with IBD. Up to 30% of IBD patients clinically exhibit abnormal liver function tests. With the increasing incidence of IBD due to economic development and lifestyle changes, the number of patients with IBD complicated by liver injury is on the rise. The mechanism of IBD complicated by liver injury is not yet clear, with unhealthy habits and environmental factors possibly being the main triggers. As a country with a high alcohol consumption rate, statistics show that 30.5% of the population in China drinks alcohol. With lifestyle improvements, people often consume high-calorie foods (such as fats) while drinking, and these combined factors are often key triggers for IBD and liver injury. The simultaneous intake of alcohol and high fat content tends to increase the permeability of the intestinal mucosal barrier, disrupt the gut-liver axis, and exacerbate acute liver damage. It is known that alcohol and high-fat diets are significant potential risk factors for promoting inflammatory liver damage, yet their specific molecular mechanisms remain unknown, and there are currently no effective drugs for treating related inflammatory liver damage clinically. Therefore, clarifying whether alcohol combined with a high-fat diet promotes inflammatory liver damage and exploring its specific mechanisms have important clinical implications for the prevention and treatment of such damage. This study uses DSS-induced colitis mice as subjects to investigate whether alcohol combined with a high-fat diet exacerbates inflammatory liver damage. It also integrates multi-omics data to explore the regulatory mechanisms of alcohol and high-fat diet on inflammatory liver damage, aiming to identify potential intervention targets to provide a theoretical basis for related drug development.

ORGANISM(S): Mus

PROVIDER: GSE285536 | GEO | 2025/12/30

REPOSITORIES: GEO

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Project description:This study tested a hypothesis that a population-based approach may identify genetic background-dependent and -independent genes/pathways that modulate alcohol-induced liver injury. A sub-chronic (4 weeks) intra-gastric alcohol infusion (up to 27 g/kg/day) model was used to control for alcohol intake in 15 genetically diverse inbred mouse strains. Urine, serum and liver markers of alcoholic steato-hepatitis were assessed and a wide range of liver damage was observed across the panel. Gene expression profiling was performed on liver tissue collected at the end of the study and statistical models, with strain, degree of liver injury, treatment, and their interaction terms as factors, were used to select transcripts associated with strain-dependent and -independent effects of alcohol on the liver. Translational control of hepatic protein synthesis, related to eukaryotic initiation factors (eiFs) and accessory proteins, was identified as genetic background-independent mode of alcohol-induced liver injury. Interestingly, immune response-related transcription factors signal transducer and activator of transcription 1 (Stat1) and nuclear factor, interleukin 3 regulated (Nfil3/E4bp4) are likely determinants of genetic background-dependent responses to liver injury and alcohol treatment, respectively. Our data demonstrate that a multistrain approach provides critical mechanistic information for understanding genetic factors influencing alcohol toxicity and facilitate identification of novel targets of therapeutic intervention. A high-fat diet or EtOH-containing high-fat diet was administered to 15 strains of mice via gastric tube for 28 days. 3 replicates per strain/diet. Inter-batch normalization was carried out using the ComBat procedure. The supplementary file 'GSE20052_Readme.txt' contains a description of the replicates used for normalization. The 'GSE20052_US14702406_25148681*' files linked to the GSE20052 record are the raw data files for the replicates.

Project description:Intake of high-protein (HP) diets has increased over the last years, mainly due to their popularity for body weight control. Liver is the main organ handling ingested macronutrients and it is associated with the beginning of different pathologies. We aimed to deepen our knowledge on molecular pathways affected by long-term intake of an HP diet. We performed a transcriptome analysis on liver of rats chronically fed with a casein-rich HP diet and analyzed molecular parameters related to liver injury. Chronic increase in the dietary protein/carbohydrate ratio up-regulated processes related with amino acid uptake/metabolism and lipid synthesis, promoting a molecular environment indicative of hepatic triacylglycerol (TG) deposition. Moreover, changes in expression of genes involved in acidâbase maintenance and oxidative stress indicate alterations in the pH balance due to the high acid load of the diet, which has been linked to liver/health damage. Up-regulation of immune-related genes was also observed. In concordance with changes at gene expression level, we observed increased liver TG content and increased serum markers of hepatic injury/inflammation (aspartate transaminase, C-reactive protein and TNF-alpha). Moreover, the HP diet strongly increased hepatic mRNA and protein levels of HSP90, a marker of liver injury. Thus, we show for the first time that long-term consumption of an HP diet, resulting in a high acid load, results in a hepatic transcriptome signature reflecting increased TG deposition and increased signs of health risk (increased inflammation, alterations in the acidâbase equilibrium and oxidative stress). Persistence of this altered metabolic status could have unhealthy consequences. Wistar wildtype male rats, aged 8 weeks, received a low fat diet, high protein or high fat diet for 4 months. After sacrification, livers were dissected, and immediately snap frozen in liquid nitrogen. Total RNA was isolated, quantified and qualified, and subsequently used for global gene expression profiling using Agilent 4x44K microarrays.

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Study on the effects and mechanisms of alcohol combined with high-fat diet in promoting enteritis-induced liver injury

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