New targets for NAFLD

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a growing cause of chronic liver disease worldwide. It is characterised by steatosis, liver inflammation, hepatocellular injury and progressive fibrosis. Several preclinical models (dietary and genetic animal models) of NAFLD have deepened our understanding of its aetiology and pathophysiology. Despite the progress made, there are currently no effective treatments for NAFLD. In this review, we will provide an update on the known molecular pathways involved in the pathophysiology of NAFLD and on ongoing studies of new therapeutic targets.

Keywords: ACC, acetyl-CoA carboxylase; ASK1, apoptosis signal-regulating kinase 1; CAP, controlled attenuation parameter; ChREBP; ChREBP, carbohydrate responsive element–binding protein; FAS, fatty acid synthase; FFA, free fatty acid; FGF21, fibroblast growth factor-21; FXR; FXR, farnesoid X receptor; GGT, gamma glutamyltransferase; HCC, hepatocellular carcinoma; HFD, high-fat diet; HSC, hepatic stellate cells; HSL, hormone-sensitive lipase; HVPG, hepatic venous pressure gradient; IL-, interleukin-; JNK, c-Jun N-terminal kinase; LXR; LXR, liver X receptor; MCD, methionine- and choline-deficient; MUFA, monounsaturated fatty acids; NAFLD; NAFLD, non-alcoholic fatty liver disease; NASH; NASH, non-alcoholic steatohepatitis; NEFA; NEFA, non-esterified fatty acid; PPARα; PPARα, peroxisome proliferator-activated receptor-α; PUFAs, polyunsaturated fatty acids; PY, persons/years; Phf2, histone demethylase plant homeodomain finger 2; RCT, randomised controlled trial; SCD1, stearoyl-CoA desaturase-1; SFA, saturated fatty acid; SREBP-1c; SREBP-1c, sterol regulatory element–binding protein-1c; TCA, tricarboxylic acid; TLR4, Toll-like receptor 4; TNF-α, tumour necrosis factor-α; VLDL, very low-density lipoprotein; animal models; glucotoxicity; lipotoxicity.

Fig. 1

Insulin resistance and NAFLD. During insulin resistance, glucose delivery increases and activates ChREBP that leads to an increase in glycolysis and de novo lipogenesis. Defective hepatic insulin signalling impairs the ability of insulin to inhibit gluconeogenesis while still increasing SREBP1-c-mediated de novo lipogenesis. Liver PPARα activity and β-oxidation are decreased in NAFLD, thereby participating in the accumulation of triglycerides in the liver. Peripheral insulin resistance leads to an incomplete suppression of adipose tissue lipolysis increasing the liberation of free fatty acids and glycerol that reach the liver to increase gluconeogenesis. During insulin resistance and NAFLD, the levels of adipose tissue-producing adiponectin decreased; thus, decreasing β-oxidation and increasing de novo lipogenesis and gluconeogenesis. Metabolic pathways that are increased or decreased during NAFLD/insulin resistance are labelled with green or red dots, respectively. ACC, acetyl-CoA carboxylase; ACL, ATP-citrate lyase; ChREBP, carbohydrate responsive element–binding protein; Cpt, carnitine palmitoyltransferase; DAG, diacylglycerol; DPAT, diacylglycerol phosphate acyltransferase; DNL, de novo lipogenesis; FA, fatty acid; FAS, fatty acid synthase; FBPase, fructose 1,6-bisphophatase; FFA, free fatty acid; GK, glucokinase; GPAT, glycerol-3-phosphate acyltransferase; GS, glycogen synthase; LPK, L-type pyruvate kinase; MUFA, monounsaturated fatty acid; NAFLD, non-alcoholic fatty liver disease; PEPCK, phosphoenolpyruvate carboxykinase; PK, pyruvate kinase; PPARα, peroxisome proliferator-activated receptor α; SCD1, stearoyl-CoA desaturase 1; SREBP-1c, sterol regulatory element–binding protein-1c; TAG, triacylglycerol; VLDL, very low-density lipoprotein.

Fig. 2

Therapeutic targets in NAFLD and NASH. Therapeutic approaches in NAFLD target either the metabolism to decrease liver fat deposition or apoptosis and fibrosis to limit the progression of NAFLD. Metabolic treatments mostly target de novo lipogenesis, β-oxidation and bile acid metabolism. They can act indirectly by inhibiting enzymes that control de novo lipogenesis (inhibitors of FAS, ACC, SCD, DGAT) or be direct analogues (or antagonists) for nuclear receptors involved in de novo lipogenesis, β-oxidation and bile acid metabolism. Complications of NAFLD (inflammation, apoptosis and fibrosis) are targeted by different molecules. They have the ability to limit the activation of Kupffer cells and stellate cells by different mechanisms, thereby preventing collagen deposition and fibrosis. ACC, acetyl-CoA carboxylase; ACL, ATP-citrate lyase; AOC3, amine oxidase copper containing 3; ChREBP, carbohydrate responsive element–binding protein; Cpt, carnitine palmitoyltransferase; CYP7A1, cytochrome P450 7A1; DAG, diacylglycerol; DGAT, diacylglycerol acyltransferase; DPAT, diacylglycerol phosphate acyltransferase; ER, endoplasmic reticulum; FAS, fatty acid synthase; FXR, farnesoid X receptor; GPAT, glycerol-3-phosphate acyltransferase; IL-, interleukin-; JNK, c-Jun N-terminal kinase; LXR, liver X receptor; MUFA, monounsaturated fatty acid; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; PPAR, peroxisome proliferator-activated receptor; RXR, retinoid X receptor; SCD1, stearoyl-CoA desaturase 1; TAG, triacylglycerol; TNFα, tumour necrosis factor-α.