Reduction of De Novo Lipogenesis Mediates Beneficial Effects of Isoenergetic Diets on Fatty Liver: Mechanistic Insights from the MEDEA Randomized Clinical Trial

Background: Non‐alcoholic liver steatosis (NAS) results from an imbalance between hepatic lipid storage, disposal, and partitioning. A multifactorial diet high in fiber, monounsaturated fatty acids (MUFAs), n‐6 and n‐3 polyunsaturated fatty acids (PUFAs), polyphenols, and vitamins D, E, and C reduces NAS in people with type 2 diabetes (T2D) by 40% compared to a MUFA‐rich diet. We evaluated whether dietary effects on NAS are mediated by changes in hepatic de novo lipogenesis (DNL), stearoyl‐CoA desaturase (SCD1) activity, and/or β‐ oxidation.; Methods: According to a randomized parallel group study design, 37 individuals with T2D completed an 8‐week isocaloric intervention with a MUFA diet (n = 20) or multifactorial diet (n = 17). Before and after the intervention, liver fat content was evaluated by proton magnetic resonance spectroscopy, serum triglyceride fatty acid concentrations measured by gas chromatography, plasma β‐hydroxybutyrate by enzymatic method, and DNL and SCD‐1 activity assessed by calculating the palmitic acid/linoleic acid (C16:0/C18:2 n6) and palmitoleic acid/palmitic acid (C16:1/C16:0) ratios, respectively; Results: Compared to baseline, mean ± SD DNL significantly decreased after the multifactorial diet (2.2 ± 0.8 vs.1.5 ± 0.5, p = 0.0001) but did not change after the MUFA diet (1.9 ± 1.1 vs. 1.9 ± 0.9, p = 0.949), with a significant difference between the two interventions (p = 0.004). The mean SCD‐1 activity also decreased after the multifactorial diet (0.13 ± 0.05 vs. 0.10 ± 0.03; p = 0.001), but with no significant difference between interventions (p = 0.205). Fasting plasma β‐hydroxybutyrate concentrations did not change significantly after the MUFA or multifactorial diet. Changes in the DNL index significantly and positively correlated with changes in liver fat (r = 0.426; p = 0.009). Conclusions: A diet rich in multiple beneficial dietary components (fiber, polyphenols, MUFAs, PUFAs, and other antioxidants) compared to a diet rich only in MUFAs further reduces liver fat accumulation through the inhibition of DNL. Registered under ClinicalTrials.gov no. NCT03380416.