Abstract
Lipotoxicity causes hepatic cell death and therefore plays an important role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metformin, a first-line anti-diabetic drug, has shown a potential protective effect against NAFLD. However, the underlying mechanism is still not clear. In this study, we aim to understand the molecular mechanism of the protective effect of metformin in NAFLD, focusing on lipotoxicity. Cell death was studied in HepG2 cells and primary rat hepatocytes exposed to palmitate and metformin. Metformin ameliorated palmitate-induced necrosis and apoptosis (decreased caspase-3/7 activity by 52% and 57% respectively) in HepG2 cells. Metformin also reduced palmitate-induced necrosis in primary rat hepatocytes (P < 0.05). The protective effect of metformin is not due to reducing intracellular lipid content or activation of AMPK signaling pathways. Metformin and a low concentration (0.1 μmol/L) of rotenone showed moderate inhibition on mitochondrial respiration indicated by reduced basal and maximal mitochondrial respiration and proton leak in HepG2 cells. Moreover, metformin and rotenone (0.1 μmol/L) preserved mitochondrial membrane potential in both HepG2 cells and primary rat hepatocytes. In addition, metformin and rotenone (0.1 μmol/L) also reduces reactive oxygen species (ROS) production and increase superoxide dismutase 2 (SOD2) expression. Our results establish that metformin AMPK-independently protects against palmitate-induced hepatic cell death by moderate inhibition of the mitochondrial respiratory chain, recovering mitochondrial function, decreasing cellular ROS production, and inducing SOD2 expression, indicating that metformin may have beneficial actions beyond its glucose-lowering effect and also suggests that mitochondrial complex І may be a therapeutic target in NAFLD.
Highlights
Non-alcoholic fatty liver disease (NAFLD) has emerged as one of the major health problems around the world and its prevalence coincides with the unprecedented increase of obesity in recent decades
NAFLD is characterized as increased accumulation of lipids in the liver and its severity ranges from simple steatosis to non-alcoholic steatohepatitis (NASH)
We showed that metformin protected hepatocytes from palmitate-induced cell death
Summary
Non-alcoholic fatty liver disease (NAFLD) has emerged as one of the major health problems around the world and its prevalence coincides with the unprecedented increase of obesity in recent decades. It has been shown that elevated plasma levels of non-esterified fatty acids (NEFA) are closely associated with hepatic dysfunction and the detrimental effect of surplus lipids, especially saturated fatty acids, has been termedlipotoxicity [1,2]. Both in vivo experiments and clinical studies indicated that the saturated fatty acids are more toxic compared to unsaturated fatty acids and saturated fatty acids may be one of the factors promoting the progression of steatosis to steatohepatitis [3,4]. Counteracting lipotoxicity has become one of the therapeutic targets in the treatment of NAFLD
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