ADV36 adipogenic adenovirus in human liver disease

Abstract

Obesity and liver steatosis are usually described as related diseases. Obesity is regarded as exclusive consequence of an imbalance between food intake and physical exercise, modulated by endocrine and genetic factors. Non-alcoholic fatty liver disease (NAFLD), is a condition whose natural history is related to, but not completely explained by over-nutrition, obesity and insulin resistance. There is evidence that environmental infections, and notably adipogenic adenoviruses (ADV) infections in humans, are associated not only with obesity, which is sufficiently established, but also with allied conditions, such as fatty liver. In order to elucidate the role, if any, of previous ADV36 infection in humans, we investigated association of ADV36-ADV37 seropositivity with obesity and fatty liver in humans. Moreover, the possibility that lifestyle-nutritional intervention in patients with NAFLD and different ADV36 seropositive status, achieves different clinical outcomes on ultrasound bright liver imaging, insulin resistance and obesity was challenged. ADV36 seropositive patients have a more consistent decrease in insulin resistance, fatty liver severity and body weight in comparison with ADV36 seronegative patients, indicating a greater responsiveness to nutritional intervention. These effects were not dependent on a greater pre-interventional body weight and older age. These results imply that no obvious disadvantage - and, seemingly, that some benefit - is linked to ADV36 seropositivity, at least in NAFLD. ADV36 previous infection can boost weight loss and recovery of insulin sensitivity under interventional treatment.

Keywords: Human adenovirus 36; Insulin resistance; Mediterranean diet; Non-alcoholic fatty liver disease; Obesity; Ultrasound.

Figure 1

ADV36 seropositivity prevalence increases with ageing (20-29, 30-39, 40-49, 50-59, 60-69 and ≥ 70 years) considering consecutive adult age decades in our population.

Figure 2

Odds ratios show an increased hazard of obesity associated with ADV36 seropositivity (OR = 6.879; 95%CI: 3.316-14.274), essential hypertension (OR = 2.977; 95%CI: 1.625-5.451) and insulin resistance (OR = 3.792; 95%CI: 2.052-7.006).

Figure 3

Convex ultrasound transducer with a central hole for allowing co-axial biopsy and four different specimens of liver fine needle aspirate biopsy in fatty liver performed with 20 G needle.

Figure 4

Odds ratio: Higher hazard of non-alcoholic fatty liver disease is associated with insulin resistance and obesity, and a lower non-alcoholic fatty liver disease risk is associated with ADV36 seropositivity. NAFLD: Nonalcoholic fatty liver disease.

Figure 5

Odds ratio. Increased risk of obesity (top) is associated with greater insulin resistance, C-reactive protein, and ADV37 seropositivity (Ad37⁺), whereas higher high-density lipoprotein cholesterol is associated with lower prevalence of obesity. A more consistent association of ADV37⁺, greater insulin resistance, C-reactive protein (CRP), and obesity was observed with non-alcoholic fatty liver disease (NAFLD) (bottom), whereas higher high-density lipoprotein (HDL) cholesterol was associated with a lower prevalence of NAFLD. No sex difference was found. This behavior is different, if not opposite, of that of ADV36.

Figure 6

After a comprehensive nutritional and lifestyle intervention, the improvement is more relevant in ADV36 seropositive than in ADV36 seronegative non-alcoholic fatty liver disease patients: a greater decrease of insulin resistance (homeostasis model assessment) and of overweight (body mass index) was achieved in ADV seropositive non-alcoholic fatty liver disease patients (A) and the odds of bright liver persistence is associated with lack of insulin resistance (homeostasis model assessment) and body weight (body mass index) decrease, while a relevant association with improvement, i.e., bright liver disappearance, is observed in ADV36 seropositive non-alcoholic fatty liver disease patients (B). BMI: Body mass index; HOMA: Homeostasis model assessment; NAFLD: Non-alcoholic fatty liver disease.

Figure 7

Working model to explain the antidiabetic effect of ADV36. Overall, data from suggest that, in adipose tissue, skeletal muscle, and liver of mice, ADV36 downregulates insulin signaling yet upregulates the Ras-PI3K pathway, which upregulates Glut1 and Glut4 in skeletal muscle and adipose tissue and downregulates Glut2 in liver. Furthermore, ADV36 increases adiponectin, which may activate AMPK. Collectively, this leads to greater glucose uptake by adipose tissue and skeletal muscle and reduces hepatic glucose release, which may contribute to ADV36-induced improvement in systemic glycemic control[53]. Modified from Krishnapuram et al[54].

Figure 8

Compound ADV36/ADV37 seropositivity is associated with a risk profile more similar to ADV37 seropositivity, whose effect is not blunted by ADV36 seropositivity. NAFLD: Non-alcoholic fatty liver disease.