Abstract
Hepatic steatosis often accompanies obesity and insulin resistance. The cornerstones of steatosis treatment include reducing body weight and dietary fat intake, which are marginally successful over the long term. Ad36, a human adenovirus, may offer a template to overcome these limitations. In vitro and in vivo studies collectively indicate that via its E4orf1 protein, Ad36 improves hyperglycemia, and attenuates hepatic steatosis, despite a high fat diet and without weight loss. Considering that hepatic insulin sensitivity, or the synthesis, oxidation, or export of fatty acid by hepatocytes are the key determinant of hepatic lipid storage, we determined the role of E4orf1 protein in modulating these physiological pathways. For this study, HepG2 cells, or mouse primary hepatocytes were transfected with E4orf1 or the null vector. Glucose output by hepatocytes was determined under gluconeogenic conditions (cAMP and dexamethasone, or glucagon exposure). Also, de-novo lipogenesis, palmitate oxidation, and lipid export as determined by apoB secretion were measured 48 h post transfection. Results show that compared to null vector transfected cells, E4orf1 significantly reduced glucose output in basal and gluconeogenic conditions. E4orf1 reduced de-novo lipogenesis by about 35%, increased complete fatty acid oxidation 2-fold (p<0.0001), and apoB secretion 1.5 fold(p<0.003). Response of key signaling molecules to E4orf1 transfection was in agreement with these findings. Thus, E4orf1 offers a valuable template to exogenously modulate hepatic glucose and lipid metabolism. Elucidating the underlying molecular mechanism may help develop therapeutic approaches for treating diabetes or non-alcoholic fatty liver disease(NAFLD).
Highlights
Impaired hepatic fatty acid oxidation, decreased hepatic lipid export, and increased hepatic de-novo lipogenesis (DNL), are key determinants of hepatic lipid accumulation, which may contribute to non-alcoholic fatty liver disease (NAFLD) [1,2,3,4]
The experiment was conducted in mouse primary hepatocytes, and E4orf1 suppressed glucose output compared to the null vector (p = 0.0001) (Figure 2A)
Previous animal studies showed that Ad36 improves systemic glycemic control and attenuates hepatic lipid accumulation even in presence of a high fat diet
Summary
Impaired hepatic fatty acid oxidation, decreased hepatic lipid export, and increased hepatic de-novo lipogenesis (DNL), are key determinants of hepatic lipid accumulation, which may contribute to non-alcoholic fatty liver disease (NAFLD) [1,2,3,4]. NASH is a more advanced stage of NAFLD, which includes inflammation and fibrosis in addition to lipid accumulation that is thought to further contribute to hepatic insulin resistance. Effective control of hepatic steatosis may improve insulin resistance and attenuate the progression to NAFLD or more serious complications. Weight loss and lowering dietary fat intake are the cornerstones of treatment for steatosis, yet these interventions are marginally effective in the long term [13]. Novel drugs are urgently needed for the treatment of NAFLD
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