Mechanisms of NAFLD development and therapeutic strategies

Abstract

There has been a rise in the prevalence of nonalcoholic fatty liver disease (NAFLD), paralleling a worldwide increase in diabetes and metabolic syndrome. NAFLD, a continuum of liver abnormalities from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), has a variable course but can lead to cirrhosis and liver cancer. Here we review the pathogenic and clinical features of NAFLD, its major comorbidities, clinical progression and risk of complications and in vitro and animal models of NAFLD enabling refinement of therapeutic targets that can accelerate drug development. We also discuss evolving principles of clinical trial design to evaluate drug efficacy and the emerging targets for drug development that involve either single agents or combination therapies intended to arrest or reverse disease progression.

Fig. 1|. The substrate-overload liver injury model of NASH pathogenesis.

Free fatty adds are central to the pathogenesis of NASH. Free fatty adds that originate from lipolysis of triglyceride in adipose tissue are delivered through blood to the liver. The other major contributor to the free fatty acid flux through the liver is DNL, the process by which hepatocytes convert excess carbohydrates, especially fructose, to fatty acids. The two major fates of fatty acids in hepatocytes are mitochondrial beta-oxidation and re-esterification to form triglyceride. Triglyceride can be exported into the blood as VLDL or stored in lipid droplets. Lipid droplet triglyceride undergoes regulated lipolysis to release fatty acids back into the hepatocyte free fatty acid pool. PNPLA3 participates in this lipolytic process, and a single-nucleotide variant of PNPLA3 is strongly associated with NASH progression, underscoring the importance of the regulation of this lipolysis. When the disposal of fatty acids through beta-oxidation or formation of triglyceride is overwhelmed, fatty acids can contribute to the formation of lipotoxic species that lead to ER stress, oxidant stress and inflammasome activation. These processes are responsible for the phenotype of NASH with hepatocellular injury, inflammation, stellate cell activation and progressive accumulation of excess extracellular matrix. Lifestyle modifications that include healthy eating habits and regular exercise reduce the substrate overload through decreased intake and diversion of metabolic substrates to metabolically active tissues and can thereby prevent or reverse NASH. SCD, steroyl CoA-desaturase; FAS, fatty acid synthase; NKT, natural killer T cell; T_regs, regulatory T cells; PMNs, polymorphonuclear leukocytes. Credit: Marina Corral Spence/Springer Nature

Fig. 2|. Intrahepatic drug targets in phase 2 and 3 clinical trials for NASH.

Depiction of the sites of action of drugs that are currently in phase 2 or 3 clinical trials, based on their primary locus of activity within the liver. Targets include those that regulate lipids and glucose homeostasis, and oxidant stress and mitochondrial targets in hepatocytes, inflammatory signals converge on hepatocytes, and those inflammatory signals and intracellular targets related to stellate cell activation and fibrogenesis. Gray boxes indicate disease drivers. Some targets (e.g, FXR agonists, CCR2 and CCR5 (CCR2/5) antagonist) have more than one action within the injury milieu. Agonists are indicated with a circle and antagonists with a cross. DGAT, Diacylglycerol O-acyltransferase; SCD, steroyl CoA-desaturase; THR, thyroid hormone receptor; SIRT, sirtuin; GLP, glucagon-like peptide; SGLT, sodium–glucose cotransporter; VAP, vascular adhesion protein; LPS, lipopolysaccharide; PPARα/δ/γ, peroxisome proliferator–activated receptors PPARα, PPARδ and PPARγ. Credit: Marina Corral Spence/Springer Nature

Histologic features of human NASH.

a, A schema for diagnosing NAFLD and NASH. Credit: Marina Corral Spence/Springer Nature. b, The panel of images from liver biopsies demonstrate the typical appearances of macrovesicular steatosis (fat), hepatocellular ballooning, lobular inflammation and pericellular fibrosis (arrows). As the disease progresses into cirrhosis (not shown), these features may also regress. H&E staining images were courtesy of Pierre Bedossa)