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A spotlight on pathogenesis, interactions and novel therapeutic options in NAFLD

In 2018, there have been substantial advances in our understanding of the risk factors for advanced liver disease in nonalcoholic fatty liver disease, including genetic variants and the gut microbiota. Promising results have also arisen from drugs targeting metabolic pathways involved in the progression of liver damage.

Key advances

  • Squalene epoxidase (SQLE) has a key role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma, and drugs targeting SQLE (such as terbinafine) might be considered for the treatment of this cancer2.

  • A splice variant in HSD17B13 is associated with reduced levels of liver transaminases and reduced risk of nonalcoholic steatohepatitis (NASH), fibrosis and NAFLD-related cirrhosis3.

  • Patients with NAFLD have low microbial gene richness and increased microbial genetic potential for the processing of dietary lipids and endotoxin biosynthesis, leading to hepatic inflammation and amino acid biosynthesis dysregulation4.

  • Results of the phase 2 study testing the safety and efficacy of NGM282, a non-tumorigenic analogue of fibroblast growth factor 19, revealed NGM282 was able to reduce liver-fat content, inflammation and fibrosis in patients with biopsy-proven NASH9.

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  1. 1.

    Younossi, Z. et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat. Rev. Gastroenterol. Hepatol. 15, 11–20 (2018).

  2. 2.

    Liu, D. et al. Squalene epoxidase drives NAFLD-induced hepatocellular carcinoma and is a pharmaceutical target. Sci. Transl Med. 10, eaap9840 (2018).

  3. 3.

    Abul-Husn, N. S. et al. A protein-truncating HSD17B13 variant and protection from chronic liver disease. N. Engl. J. Med. 378, 1096–1106 (2018).

  4. 4.

    Hoyles, L. et al. Molecular phenomics and metagenomics of hepatic steatosis in non-diabetic obese women. Nat. Med. 24, 1070–1080 (2018).

  5. 5.

    European Association for the Study of the Liver, European Association for the Study of Diabetes & European Association for the Study of Obesity. EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J. Hepatol. 64, 1388–1402 (2016).

  6. 6.

    Dibba, P. et al. Emerging therapeutic targets and experimental drugs for the treatment of NAFLD. Diseases 6, E83 (2018).

  7. 7.

    Arab, J. P. et al. Bile acids and nonalcoholic fatty liver disease: Molecular insights and therapeutic perspectives. Hepatology 65, 350–362 (2017).

  8. 8.

    Zhou, M. et al. Non-cell-autonomous activation of IL-6/STAT3 signaling mediates FGF19-driven hepatocarcinogenesis. Nat. Commun. 8, 15433 (2017).

  9. 9.

    Harrison, S. A. et al. NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 391, 1174–1185 (2018).

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R.Y. and E.B. are supported by grant from the EPoS (Elucidating Pathways of Steatohepatitis) consortium funded by the Horizon 2020 Framework Program of the European Union under Grant Agreement 634413.

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Competing interests

The authors declare no competing interests.

Correspondence to Elisabetta Bugianesi.

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Fig. 1: Crosstalk between NAFLD pathogenesis and treatment in 2018.