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

Abstract

Nonalcoholic 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 DNL. Hepatic DNL 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.

Keywords: De novo lipogenesis; Fructose; HFD; Liver; Metabolism; NAFLD; NASH.

Figure 1. Hepatic de novo lipogenesis

Dietary carbohydrates, lipids and proteins may be used as substrates for de novo lipogenesis. Carbohydrates are metabolized to three carbon intermediates dihydroxyacetone phosphate (DHAP) and glyceraldehyde three phosphate (GA3P) which are further metabolized to pyruvate. Pyruvate enters mitochondria to be used for energy production. When energy stores are plentiful citrate is transported to cytoplasm where by the action of ATP citrate lyase (ACL) it is converted to acetyl-CoA. Acetyl CoA carboxylase (ACC) converts acetyl-CoA to malonyl CoA. Fatty acid synthase (FAS) sequentially adds acetyl-CoA to growing fatty acid chain to form saturated fatty acids, mainly palmitate. Palmitate may be further elongated to stearate or longer fatty acids by the action of elongation of very long chain fatty acids (ELOVL6). Stearoyl CoA desaturase (SCD1) converts saturated fatty acids to monounsaturated fatty acids. Glycerol-3-phosphate acyltransferase (GPAT), adds acyl-CoA to glycerol-3 phosphate (G3P) to form lysophosphatidic acid (LPA). The enzymatic action of 1-acylglycerol-3-phosphate acyltransferase (AGPAT) adds second acyl-CoA to produce phosphatidic acid (PA), which is then dephosphorylated by Lipin1 (LPIN1) to form 1,2-diacylglycerol (DAG). Diacylglycerol acyltransferase (DGAT) converts diacylglycerols into triglycerides (TG) which may be stored in the liver or assembled into VLDL and exported to circulate in the blood. Dietary lipids or adipocyte lipolysis supplies free fatty acids which are converted in hepatocytes to acetyl-CoAs. They may be used in mitochondria for energy production or be exported back to cytosol as citrate and used for de novo lipogenesis similar to carbohydrates. Additionally, acetyl-CoA may be directly assembled into TGs by the action of DGAT bypassing the majority of enzymes involved in de novo lipogenesis. Proteins are degraded to amino acids, some of which may be used for gluconeogenesis and/or ketogenesis.

Figure 2. De novo lipogenesis is a central abnormality in NAFLD

Lambert et al., used isotope analysis to compare de novo lipogenesis and fatty acid flux in obese subjects with and without NAFLD. The proportion of hepatic triglycerides deriving from the evening meal was not different, 5% versus 5%, at the end of the study. The proportion of triglycerides synthesized from plasma FFA in low liver-fat group (52%), was significantly higher than in high liver-fat group (38%). By contrast, triglycerides synthesized via de novo lipogenesis was significantly higher in high liver-fat group (23%), compared to low liver-fat group (10%).

Figure 3. Lipogenic potential of fructose

Dietary lipids are absorbed from the intestine via lymphatic system and are equally available to all metabolically active tissue. Dietary carbohydrates are absorbed from the intestine via portal vein and directly reach the liver. More than 90% of fructose is metabolized by the liver via first pass metabolism. Fructose may directly upregulate transcriptional factors regulating de novo lipogenesis or may do so indirectly by inducing ER stress, insulin resistance and decreased mitochondrial metabolism leading to the production of uric acid and reactive oxygen species.