Hepatic mitochondrial NAD+ transporter SLC25A47 activates AMPKa mediating lipid metabolism and tumorigenesis

Background & Aims: SLC25A47 was initially identified as a mitochondrial HCC-downregulated carrier protein, but its physiological functions and transport substrates are unknown. We aimed to investigate the physiological role of SLC25A47 in hepatic metabolism. Approach & Results: In the treatment of hepatocytes with metformin, we found that metformin can transcriptionally activate the expression of Slc25a47, which is required for AMP-activated protein kinase a (AMPK alpha) phosphorylation. Slc25a47-deficient mice had increased hepatic lipid content, triglycerides, and cholesterol levels, and we found that Slc25a47 deficiency suppressed AMPKa phosphorylation and led to an increased accumulation of nuclear SREBPs, with elevated fatty acid and cholesterol biosynthetic activities. Conversely, when Slc25a47 was overexpressed in mouse liver, AMPK alpha was activated and resulted in the inhibition of lipogenesis. Moreover, using a diethylnitrosamine-induced mouse HCC model, we found that the deletion of Slc25a47 promoted HCC tumorigenesis and development through the activated mammalian target of rapamycin cascade. Employing homology modeling of SLC25A47 and virtual screening of the human metabolome database, we demonstrated that NAD+ was an endogenous substrate for SLC25A47, and the activity of NAD+-dependent sirtuin 3 declined in Slc25a47-deficient mice, followed by inactivation of AMPKa. Conclusions: Our findings reveal that SLC25A47, a hepatocyte-specific mitochondrial NAD+ transporter, is one of the pharmacological targets of metformin and regulates lipid homeostasis through AMPKa, and may serve as a potential drug target for treating NAFLD and HCC.

Automated summary

SLC25A47 plays an important role in hepatic metabolism by regulating lipid homeostasis through the phosphorylation of AMP-activated protein kinase a (AMPK alpha). Deficiency of SLC25A47 is associated with increased hepatic lipid content, triglycerides, and cholesterol levels, and promotes HCC tumorigenesis and development. SLC25A47 is also identified as one of the pharmacological targets of metformin.