Nonalcoholic fatty liver disease (NAFLD) from pathogenesis to treatment concepts in humans

Abstract

Background: Nonalcoholic fatty liver disease (NAFLD) comprises hepatic alterations with increased lipid accumulation (steatosis) without or with inflammation (nonalcoholic steatohepatitis, NASH) and/or fibrosis in the absence of other causes of liver disease. NAFLD is developing as a burgeoning health challenge, mainly due to the worldwide obesity and diabetes epidemics.

Scope of review: This review summarizes the knowledge on the pathogenesis underlying NAFLD by focusing on studies in humans and on hypercaloric nutrition, including effects of saturated fat and fructose, as well as adipose tissue dysfunction, leading to hepatic lipotoxicity, abnormal mitochondrial function, and oxidative stress, and highlights intestinal dysbiosis. These mechanisms are discussed in the context of current treatments targeting metabolic pathways and the results of related clinical trials.

Major conclusions: Recent studies have provided evidence that certain conditions, for example, the severe insulin-resistant diabetes (SIRD) subgroup (cluster) and the presence of an increasing number of gene variants, seem to predispose for excessive risk of NAFLD and its accelerated progression. Recent clinical trials have been frequently unsuccessful in halting or preventing NAFLD progression, perhaps partly due to including unselected cohorts in later stages of NAFLD. On the basis of this literature review, this study proposed screening in individuals with the highest genetic or acquired risk of disease progression, for example, the SIRD subgroup, and developing treatment concepts targeting the earliest pathophysiolgical alterations, namely, adipocyte dysfunction and insulin resistance.

Keywords: Clinical trials; Fatty liver; Fibrosis; Inflammation; Insulin resistance; Lipotoxicity.

Figure 1

Pathogenetic mechanisms driving the progression of human NAFLD and key pathways of therapeutic interventions. High caloric intake induces changes in the gut microbiota and enlargement of the adipose tissue. Diet and bariatric surgery are the main treatment strategies in this context. Gut dysbiosis is associated with disruption of intercellular tight junctions [87], which permit the translocation of bacterial lipopolysaccharide (LPS) into the systemic circulation and increase alcohol-producing bacteria [85]. The patatin-like phospholipase domain-containing protein 3 (PNPLA3) genetic variant increases adipose tissue lipolysis [17], increasing the flux of substrates and signaling molecules to the liver [92]. Adipose tissue–liver cross talk is further mediated through the secretion of exosomes [97] and adipokines [94]. Steatotic hepatocytes are characterized by a potentially upregulated uptake of FFA. Additionally, enhanced DNL converts acetyl-CoA to new fatty acids [109,112]. The genetic variant of the gene glucokinase regulatory protein (GCKR) contributes to elevated DNL, through increase in substrates availability [43]. In this context, mitochondrial fatty acid oxidation is upregulated [121]. Export of triglycerides as VLDL particles is compromised through reduced lipidation of microsomal triglyceride transfer protein (MTTP), the enzyme that catalyzes the lipidation of apolipoprotein B100 (apoB100) [138]. The transmembrane 6 superfamily member 2 (TM6SF2) genetic variant further attenuates the ability of hepatocytes to mobilize neutral lipids for the VLDL assembly [38]. Mitochondrial pyruvate carrier inhibitors (MPCi) decrease carbon flow into the tricarboxylic acid (TCA) cycle and therefore alter the ability of hepatic mitochondria to fuel DNL. A number of further pharmacological agents including fibroblast growth factor agonists (FGF21a), peroxisome proliferator-activated receptor (PPAR) ɑ agonists (PPARαa), thyroid hormone receptor-β agonists (THR-βa), and farnesoid X receptor agonists (FXRa) mainly aim to augment fatty acid oxidation, and DNL is targeted by ketohexokinase inhibitors (KHKi), stearoyl-CoA desaturase 1 inhibitors (SCD-1i), mitochondrial pyruvate carrier inhibitors (MPCi), and FXRa and acetyl coenzyme A carboxylase inhibitors (ACC1/2i). Following progression to NASH, production of sn-1,2-DAG and sphingolipids is favored. In NASH, the sn-1,2-DAG–PKCε pathway tightly correlates with hepatic insulin resistance [115]; hepatic dihydroceramides correlate with hepatic oxidative stress and inflammation [118]. Following progression to NASH, mitochondrial flexibility is lost, leading to decreased fatty acid oxidation [121] and oxidative stress and then inflammation [118], leading to hepatocytes apoptosis. Resident macrophage cells in the liver, the Kupffer cells, are increased and release proinflammatory cytokines [143]. Finally, HSC activation is regarded as a key initiating event in hepatic fibrogenesis, with activated HSC being characterized by enhanced extracellular matrix (ECM) production. Among other factors, the transforming growth factor β (TGF- β) initiates ECM gene expression in quiescent HSC [148]. Chemokine receptor (CCR2/5) antagonists and pan-PPARa mainly exert antifibrotic properties. ACC 1/2i, acetyl coenzyme A carboxylase 1/2 inhibitors; a: agonists, apoB100, apolipoprotein B100; βox, β oxidation; CER, ceramides; ChREBP, carbohydrate regulatory element binding protein; CCR, chemokine receptor; CD36, Cluster of differentiation 36; CPT1, carnitine palmitoyltransferase 1; DAG, diacylglycerols; DNL, de novo lipogenesis; ER, endoplasmic reticulum; ECM, extracellular matrix; Fa-CoA, fatty acyl-CoA; FATP, fatty acid transporters; FGF, fibroblast growth factor; FFA, free fatty acids; fruc, fructose; FXR, farnesoid X receptor; GCKR, glucokinase regulatory protein; GLP-1 RA, glucagon-like peptide 1 receptor agonists (GLP-1 RA); HC, hepatocyte; HSCs, hepatic stellate cells; i, inhibitors; IL-1β, interleukin 1β; IL-6, interleukin 6; IL-6R, interleukin 6 receptro; IR, insulin receptor; JNK, c-Jun N-terminal kinase; KHKi, ketohexokinase inhibitors; LD, lipid droplet; LPS, lipopolysaccharide; MPCi, mitochondrial pyruvate carrier inhibitors; MTTP, microsomal triglyceride transfer protein; NF-κB: nuclear factor κ-light-chain-enhancer of activated B cells; PNPLA3, patatin-like phospholipase domain-containing protein 3; PPAR, peroxisome proliferator-activated receptor; pyr, pyruvate, SCD-1i, stearoyl-CoA desaturase 1 inhibitors; SGLT-2i, sodium glucose cotransporter-2 inhibitors; SREBP1c, sterol regulatory element binding protein 1c; TAG, triacylglycerol; TCA, tricarboxylic acid; TGF-β, transforming growth factor-β; THR, thyroid hormone receptor; TLR-4, toll-like receptor-4; TNF-α, tumor necrosis factor-α; TNFR, tumor necrosis factor receptor; TM6SF2, transmembrane 6 superfamily member 2; VLDL, very low density lipoprotein.