Higher dietary fructose is associated with impaired hepatic adenosine triphosphate homeostasis in obese individuals with type 2 diabetes

Abstract

Fructose consumption predicts increased hepatic fibrosis in those with nonalcoholic fatty liver disease (NAFLD). Due to its ability to lower hepatic adenosine triphosphate (ATP) levels, habitual fructose consumption could result in more hepatic ATP depletion and impaired ATP recovery. The degree of ATP depletion following an intravenous fructose challenge test in low versus high fructose consumers was assessed. We evaluated diabetic adults enrolled in the Look AHEAD Fatty Liver Ancillary Study (n=244) for whom dietary fructose consumption estimated by a 130-item Food Frequency questionnaire, hepatic ATP measured by phosphorus MRS (31P MRS) and uric acid (UA) levels were performed (n=105). In a subset of participants (n=25), an intravenous fructose challenge was utilized to assess change in hepatic ATP content. The relationships between dietary fructose, UA and hepatic ATP depletion at baseline and following intravenous fructose challenge was evaluated in low (<15 g/d) vs. high (≥15 g/d) fructose consumers. High dietary fructose consumers had slightly lower baseline hepatic ATP levels and a greater absolute change in hepatic α-ATP/Pi ratio (0.08 vs. 0.03, p=0.05) and γ-ATP /Pi ratio following an intravenous fructose challenge (0.03 vs. 0.06, p=0.06). Patients with high UA (≥5.5 mg/dl) showed a lower minimum liver ATP/Pi ratio post-fructose challenge (4.5 vs. 7.0, p = 0.04). Conclusions High fructose consumption depletes hepatic ATP and impairs recovery from ATP depletion following an intravenous fructose challenge. Subjects with high UA show a greater nadir in hepatic ATP in response to fructose. Both high dietary fructose intake and elevated UA level may predict more severe hepatic ATP depletion in response to fructose and hence may be risk factors for the development and progression of NAFLD.

The rate of production of uric acid by hepatocytes is a sensitive index of compromised cell ATP homeostasis

“…Accordingly, other mechanisms must account for the association between hyperuricemia and insulin resistance. Diet-induced insulin resistance is a possible explanation for the association between serum urate and insulin resistance (1,5). During consumption of high-carbohydrate diets, the liver is exposed to high portal vein concentrations of glucose and/or fructose, which cause elevation in hepatic organic phosphate esters and activation of the transcription factor ChREBP-Mlx (3,6).…”

“…1). However, whether dietary fructose contributes to hyperuricemia in liver disease remains debated (1,33,40).Studies in humans have reported low hepatic ATP in obesity (10) and inverse correlations between hepatic steatosis or hepatic insulin resistance and hepatocellular P i or ATP levels (32). Accordingly, compromised hepatic P i or ATP homeostasis is a possible link between NAFLD and hyperuricemia.…”

“…1). However, whether dietary fructose contributes to hyperuricemia in liver disease remains debated (1,33,40).…”

“…Lifestyle factors linked to hyperuricemia include obesity and consumption of fructose or ethanol (1,39,43). Of these, fructose has been the most extensively studied from systemic or hepatic vein urate levels in humans after administration of fructose (15,22,23) and from dynamic changes in hepatic ATP and inorganic phosphate (P i ) concentration in human and animal models (21,22,34).…”

Fructose Consumption in the Development of Obesity and the Effects of Different Protocols of Physical Exercise on the Hepatic Metabolism

“…All these mechanisms initially triggered by the transport of fructose into the hepatocyte are extremely relevant and contribute to the development of diseases such as hyperglycaemia, gout, endothelial inflammation and arterial hypertension [2,31].…”