Hepatic De Novo Lipogenesis and Regulation of Metabolism by James M. Ntambi

Author:James M. Ntambi
Language: eng
Format: epub
Publisher: Springer International Publishing, Cham

4 Role of Delta 5 (Δ5) and Delta 6 (Δ6) Desaturases in NAFLD

Livers of obese patients with NAFLD show depletion in the concentration of long-chain poly-unsaturated fatty acids (LCPUFA ) especially the n-3 and n-6 series of TG (Araya et al. 2004, 2010). In particular, a strong decrease of arachidonic acid (AA; 20:4, n-6), eicosapentaenoic acid (EPA; 20:5, n-3) and docosahexaenoic acid (DHA; 22:6, n-3) was observed in hepatic steatosis and steatohepatitis (Araya et al. 2004). Depletion of such fatty acids may be responsible for the progression of the disease leading to cirrhosis (Gormaz et al. 2010). Modification in the availability of LCPUFA has also been associated with numerous other metabolic pathologies often associated with NAFLD such as cardio-vascular diseases, obesity, type II diabetes and metabolic syndrome (Gormaz et al. 2010). LCPUFA are formed by series of desaturations and elongations. Δ5 and Δ6 desaturases are the key desaturases in this process catalyzing the synthesis of n-3 and n-6 LCPUFA (Vessby et al. 2002). The 18:2(n-6) and 18:3(n-3) are desaturated by the Δ6 desaturase to form the 18:3(n-6) and 18:4(n-3) while the Δ5 desaturase will form the AA, EPA and DHA. In this process, the Δ6 desaturase is the rate limiting enzyme (Lenihan-Geels et al. 2013).

If the role of SCD1 in the development of NASH has been clearly established, the roles of the Δ5 and Δ6 desaturases appear more complex. In a study published in 2005, Tovar and collaborators showed that feeding hyperinsulinemic obese Zucker fa/fa rats with Soy protein decreases liver steatosis and lipotoxicity. This is associated with a potent inhibition of both Δ5 and Δ6 mRNA levels (40 % and 69 % respectively) (Tovar et al. 2005). However liver of mice fed with methionine and choline deficient diet (MCD), a nutritional model of steatohepatitis displays a significant increase in Δ5 and Δ6 desaturases mRNA (Larter et al. 2008). In these studies, the type of hepatic LCPUFA was not evaluated. Recently, a study performed in liver biopsies of NASH patients showed a clear increased in both Δ5 and Δ6 desaturases mRNA expression. This was associated with an impaired desaturation of ω3 and ω6 fatty acids, with an increase in the ω6:ω3 ratio and a reduction in the ω3 desaturation index (Lopez-Vicario et al. 2014). Several other studies performed in obese NAFLD patients also revealed a decrease in Δ5 and Δ6 desaturases activities and an increase in the ω6:ω3 ratio (Araya et al. 2004, 2010; Kotronen et al. 2009). Interestingly, it was recently showed that the decrease in Δ6 desaturase expression is associated with an up-regulation of miR-140, and miR2885, two miRNA previously associated with hepatic disorders and NAFLD (Fatima et al. 2014).

The molecular mechanisms of LCPUFA depletion on NAFLD development can be explained by the effect of these fatty acids on the transcription factors involved in lipogenesis and β-oxydation (Pettinelli et al. 2009). LCPUFA inhibits the expression of both ChREBP (Dentin et al. 2005) and SREBP-1c (Hannah et al. 2001), two transcription factors known to activate lipogenic genes expression in response to sugar and insulin respectively.

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