Shedding light on BASH: A novel experimental model of advanced liver damage

Background & Aims:

Based on recent clinical studies it has been suggested to refer patients with an intermediate alcohol drinking pattern and with signs of metabolic risk, including obesity and type 2 Diabetes Mellitus, i.e. clinical features of both alcoholic and non-alcoholic steatohepatitis as BASH. Yet, BASH is not well described and presents a large grey area in the field of Hepatology with a huge unmet need of pre-clinical and clinical studies as well as new innovative experimental animal models.

Methods:

C57BL/6 female mice received 10%v/v alcohol in sweetened drinking water in combination with a Western diet (WD) up to 23 weeks (BASH model). Mice receiving either only sweetened alcohol or only WD were used as controls. Serum markers of liver damage, liver and epididymal white adipose tissue (eWAT) histology, hepatic inflammation and fibrosis progression were analysed in detail.

Results:

Animals fed with our novel experimental BASH model elicited a significant increase in the body-mass index (BMI) accompanied by a pronounced hypertrophy of adipocytes, as well as massive infiltration of macrophages, and robust collagen deposition in eWAT.

Moreover, progressive metabolic perturbations characterized by hypercholesterolemia and fasting hyperglycemia were found in the BASH group. In our experimental model, alcohol potentiated the effect of WD with regard to dramatic hepatomegaly, hepatocyte enlargement, profound hepatic steatosis and drastically increased levels of hepatic triglycerides. Significant liver damage was characterized by elevated plasma ALT and LDH levels, positive TUNEL staining and compensatory hepatic proliferation.

Notably, the BASH feeding also resulted in significant lobular inflammation and intrahepatic accumulation of CD45, CD11b and F4/80-positive immune cells and upregulated mRNA expression of TNFα and CCl2.

Importantly, BASH – mice exhibited advanced hepatic fibrosis, collagen accumulation, activation of hepatic stellate cells (HSC) and upregulation of Collagen IA1 and MCP-1 transcripts.

Conclusions:

Our novel model of BASH displays enhanced obesity, glucose intolerance, liver damage, prominent steatohepatitis and hepatic fibrosis, as well as inflammation and fibrosis in the eWAT tissue. Altogether, the BASH model perfectly mimics all histological, metabolic, transcriptomic gene signatures of human BASH and therefore it can facilitate preclinical development of therapeutic targets in the future.