Role of Dietary Fructose and Hepatic De Novo Lipogenesis in Fatty Liver Disease

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a liver manifestation of metabolic syndrome. Overconsumption of high-fat diet (HFD) and increased intake of sugar sweetened beverages are major risk-factors for development of NAFLD. Today the most commonly consumed sugar is high fructose corn syrup. Hepatic lipids may be derived from dietary intake, esterification of plasma free fatty acids (FFA) or hepatic de novo lipogenesis (DNL). A central abnormality in NAFLD is enhanced de novo lipogenesis. Hepatic de novo lipogenesis is increased in individuals with NAFLD, while the contribution of dietary fat and plasma FFA to hepatic lipids is not significantly altered. The importance of DNL in NAFLD is further established in mouse studies with knockout of genes involved in this process. Dietary fructose increases levels of enzymes involved in DNL even more strongly than HFD. Several properties of fructose metabolism make it particularly lipogenic. Fructose is absorbed via portal vein and delivered to the liver in much higher concentrations as compared to other tissues. Fructose increases protein levels of all DNL enzymes during its conversion into triglycerides. Additionally, fructose supports lipogenesis in the setting of insulin resistance as fructose does not require insulin for its metabolism and it directly stimulates SREBP1c, a major transcriptional regulator of DNL. Fructose also leads to ATP depletion and suppression of mitochondrial fatty acid oxidation resulting in increased production of reactive oxygen species. Furthermore fructose promotes ER stress and uric acid formation, additional insulin independent pathways leading to DNL. In summary, fructose metabolism supports DNL more strongly than HFD and hepatic DNL is a central abnormality in NAFLD. Disrupting fructose metabolism in the liver may provide a new therapeutic option for the treatment of NAFLD.

Divergent effects of glucose and fructose on hepatic lipogenesis and insulin signaling

“…Fructose metabolism is more rapid than glucose metabolism (7), which may help to explain why fructose phosphorylation to fructose-1 phosphate in the liver has been associated with ATP depletion (8). The biggest difference may be in their lipogenic potential, as fructose robustly increases the expression of enzymes involved in fatty acid synthesis (9). Indeed, tracer studies show that fructose is incorporated into both glycerol and free fatty acids, while glucose is not converted into free fatty acids, at least acutely (10).…”

“…A primary abnormality in NAFLD may be increased hepatic de novo lipogenesis (9). While both monosaccharides may support lipogenesis, it is unclear whether both sugars lead to the formation of the same types of lipids or whether the magnitude of lipogenesis is the primary difference between fructose versus glucose supplementation.…”

Similarities and interactions between the ageing process and high chronic intake of added sugars

“…The appearance of NAFLD seems then more related to environmental factors than to intrinsic ageing, but the capacity to cope with the disease decreases with age (113) . Indeed, as previously described, fructose is able to disturb fatty acid metabolism, promoting NAFLD development, even in young individuals (114) . HCIAS is recognised as an important risk factor for NAFLD development (115)(116)(117) .…”

Non-alcoholic fatty liver disease: an emerging driving force in chronic kidney disease

“…Increased consumption of dietary fructose may not only increase hepatic de novo lipogenesis 36 , increasing risk of NASH, but may also increase serum uric acid concentrations 37 . Hyperuricemia may not only increase risk of gout but urinary excretion of uric acid may also damage the kidneys further in patients susceptible to CKD development 37 .…”

“…Increased consumption of dietary fructose may not only increase hepatic de novo lipogenesis 36 , increasing risk of NASH, but may also increase serum uric acid concentrations 37 . Hyperuricemia may not only increase risk of gout but urinary excretion of uric acid may also damage the kidneys further in patients susceptible to CKD development 37 . With increased dietary calorie intake, and net positive energy balance, expansion of intra-abdominal visceral adipose tissue releases increased amounts of NEFAs and proinflammatory molecules into the vasculature 38,39 .…”