IMM‐H007, a new therapeutic candidate for nonalcoholic fatty liver disease, improves hepatic steatosis in hamsters fed a high‐fat diet

Nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disease in humans, is characterized by accumulation of triglycerides in hepatocytes. We tested whether 2′,3′,5′-tri-acetyl-N6-(3-hydroxylaniline) adenosine (IMM-H007) can eliminate hepatic steatosis in hamsters fed a high-fat diet (HFD), as a model of NAFLD. Compared with HFD-only controls, IMM-H007 treatment significantly lowered serum levels of triglyceride, total cholesterol, and free fatty acids in hamsters fed the HFD, with a prominent decrease in levels of serum transaminases and fasting insulin, without affecting fasting glucose levels. Moreover, 1H-MRI and histopathological analysis revealed that hepatic-lipid accumulation and fibrosis were improved by IMM-H007 treatment. These changes were accompanied by improvement of insulin resistance and oxidative stress, and attenuation of inflammation. IMM-H007 reduced expression of proteins involved in uptake of hepatic fatty acids and lipogenesis, and increased VLDL secretion and expression of proteins responsible for fatty-acid oxidation and autophagy. In studies in vivo, IMM-H007 inhibited fatty-acid import into hepatocytes and liver lipogenesis, and concomitantly stimulated fatty-acid oxidation, autophagy, and export of hepatic lipids. These data suggest that IMM-H007 resolves hepatic steatosis in HFD-fed hamsters by regulation of lipid metabolism. Thus, IMM-H007 has therapeutic potential for NAFLD.