CE17 - Recherche translationnelle en santé

Hepatic sphingolipids in NAFLD: from liver biosynthesis to metabolic consequences – SONIC

Submission summary

Non-alcoholic fatty liver disease (NAFLD) encompasses a wide range of pathologies from steatosis to non-alcoholic steatohepatitis (NASH), fibrosis and finally cirrhosis. It is a very common pathology during type 2 diabetes (T2D), resulting in excess mortality. NAFLD also promotes the development of T2D and contributes to worsening glycemic control. Both T2D and NAFLD are characterized by insulin resistance and inflammation. The lipid species derived from palmitate called sphingolipids and in particular the ceramide family are known to induce insulin resistance and inflammation within the tissues and could be a common element to both pathologies. We have shown (Szpigel et al., Diabetologia, 2017) that the plasma of subjects with T2D had a high concentration of dihydroceramides (DHCer) compared to control subjects or those with type 1 diabetes. On the other hand our preliminary results in DT2 subjects, show that plasma concentrations of DHCer are positively correlated with hepatic steatosis and inflammation. DHCer species found elevated in plasma (16: 0 and 18: 0) suggest an hepatic origin. Hepatic lipogenesis, which synthesizes palmitate for the synthesis of DHCer, is also stimulated in patients with NAFLD. We therefore hypothesize that during NAFLDs, hepatic DHCer biosynthesis is enhanced by the activation of lipogenesis. DHCer could, in the liver and after export to insulin-sensitive peripheral tissues in lipoproteins or microparticles, have effects (inflammation, endoplasmic reticulum stress, oxidative stress, insulin resistance) that contribute to the progression of NAFLD and the appearance of T2D.
To test these hypotheses, we will conduct in vitro and in vivo studies in animals and humans with three objectives: i) to study the role of hepatic lipogenesis in the synthesis of sphingolipids and DHCer, ii) to determine the nature of circulating particles enriched with DHCer, iii) to analyze the role of DHCer on hepatic and peripheral insulin resistance and inflammation and the underlying mechanisms. In in vitro studies on primary rodent and human hepatocytes, we will overexpress by an adenoviral technique SREBP-1c, a major lipogenic factor, and evaluate the biosynthesis of sphingolipids. We will also use a pharmacological agent to inhibit lipogenesis in vitro. In vivo we will use an adenovirus expressing a dominant negative form of SREBP-1c in obese steatotic (ob / ob) mice. We will study by lipidomic analysis the concentrations of sphingolipids including DHCer. In men, studies will be based on two cohorts of T2D patients: DIACART (already existing) and NADRANK (in the recruitment phase). We will evaluate whether hepatic lipogenesis enzyme expression is correlated with hepatic and circulating sphingolipid concentrations at different stages of NAFLD. We will also evaluate in which structures, lipoproteins and / or microparticles circulate the DHCer in the plasma. We will then study the effect of these lipids on insulin signaling in hepatocytes, myocytes, adipocytes and the mechanisms involved (inflammation, RE stress, ...). Finally, we will investigate whether DHCer-enriched lipoproteins / microparticles can replicate their cellular effects on insulin target tissues. This translational project could highlight a role for DHcer in the development of NAFLDs and NAFLD-induced DT2 and describe their mechanisms. This could open new clinical perspectives on the one hand in terms of biomarkers of steatosis and on the other hand in terms of therapies targeting either the synthesis of these lipids or the involved cellular mechanisms.

Project coordination


The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.



Help of the ANR 334,800 euros
Beginning and duration of the scientific project: - 36 Months

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