Abstract
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.
Highlights
The first stage of metabolic-associated fatty liver disease (MAFLD, previously referred to as non-alcoholic fatty liver disease) is characterized by hepatic triglyceride accumulation, known as steatosis [1]
To study the direct effect of butyrate on early-stage Metabolic-associated fatty liver disease (MAFLD), this phenotype was first induced in healthy murine precision-cut liver slices
Culture of precision-cut liver slices (PCLSs) with concentrations of 36 mM glucose, 5 mM fructose, 240 μM palmitate, 480 μM oleate and 100 nM insulin (High-GFIPO; as previously used in rat PCLSs [34]), resulted in a 2-fold increase in triglyceride content after 48 h compared to the control medium (Supplementary Figure S1A)
Summary
The first stage of metabolic-associated fatty liver disease (MAFLD, previously referred to as non-alcoholic fatty liver disease) is characterized by hepatic triglyceride accumulation, known as steatosis [1]. While the pathology has surpassed a global prevalence of 25%, this stage often goes unnoticed in patients [1,2]. It is the progression of the disease to an inflammatory state called non-alcoholic steatohepatitis and beyond, that places the more obvious burden on patients, healthcare and the economy [3,4]. As the hepatic manifestation of obesity, MAFLD is closely related to metabolic syndrome.
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