Abstract

Background:

The mechanisms contributing to the progression to NASH in patients with NAFLD are unclear. Our central hypothesis is that the inability of hepatic mitochondria to enhance nutrient oxidation in the setting of nutrient oversupply plays a key role in the progression of liver disease in NAFLD. The aim of this study was to explore the relationship between adipose tissue insulin resistance (IR), liver fat, and in vivo hepatic mitochondrial function.

Methods:

Patients with BMI≥25kg/m², without diabetes were included in the study. Patients underwent a 2-hour oral glucose tolerance test (OGTT) and a liver proton magnetic resonance spectroscopy (¹H-MRS) to measure liver fat. Adipose tissue IR was estimated during a fasting period as AdipoIR: fasting insulin x free fatty acids (FFA) and in the postprandial period as insulin-mediated suppression of FFA during an OGTT. In vivo hepatic mitochondrial ATP levels were measured by phosphorus (³¹P)-MRS at baseline and every 30 minutes during a 2-hour oral fructose (75 grams) challenge (OFC). Due to unregulated phosphorylation of fructose upon entering hepatocytes, the OFC provides a dynamic measurement of hepatic ATP consumption and re-synthesis as a surrogate marker of mitochondrial function. Hepatic ATP levels were estimated as β-ATP/total phosphorus.

Results:

A total of 37 patients were recruited (54±11 years; 43% male/57% female; BMI: 34.4±6.3 kg/m²; NAFLD: 51%). No differences were found in basal hepatic ATP levels in patients with or without NAFLD (p=0.44). Similarly, we did not observe any difference in basal hepatic ATP levels with increasing levels of adipose tissue IR (p=0.42). After the OFC, no differences were observed in changes in hepatic ATP levels in patients with vs. without NAFLD (p=0.67) or based on quartiles of liver fat (Figure 1A). However, changes in hepatic ATP levels after the OFC were significantly different among groups defined by quartiles of adipose tissue IR (Figure 1B-C). These differences were more pronounced when adipose tissue IR was measured during fasting (i.e., Adipo-IR) than the postprandial state. Patients on the highest quartile of adipose tissue IR showed no consumption of ATP after the OFC, but rather an overall increase in ATP levels over time. Adipo-IR significantly correlated with changes of hepatic ATP after the OFC (-0.52, p =0.001).

Conclusion:

Patients with increased adipose tissue IR, particularly in the fasting state, showed an overcompensatory hepatic mitochondrial response, characterized by an increase in hepatic ATP levels after fructose consumption. This suggests that chronic elevated of fasting FFA lead a compensatory increase of hepatic mitochondrial oxidation capacity. At what point this compensation is overwhelmed leading to inflammation and lipotoxicity remains to be determined.