Current Therapeutical Approaches Targeting Lipid Metabolism in NAFLD

Abstract

Nonalcoholic fatty liver disease (NAFLD, including nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH)) is a high-prevalence disorder, affecting about 1 billion people, which can evolve to more severe conditions like cirrhosis or hepatocellular carcinoma. NAFLD is often concomitant with conditions of the metabolic syndrome, such as central obesity and insulin-resistance, but a specific drug able to revert NAFL and prevent its evolution towards NASH is still lacking. With the liver being a key organ in metabolic processes, the potential therapeutic strategies are many, and range from directly targeting the lipid metabolism to the prevention of tissue inflammation. However, side effects have been reported for the drugs tested up to now. In this review, different approaches to the treatment of NAFLD are presented, including newer therapies and ongoing clinical trials. Particular focus is placed on the reverse cholesterol transport system and on the agonists for nuclear factors like PPAR and FXR, but also drugs initially developed for other conditions such as incretins and thyromimetics along with validated natural compounds that have anti-inflammatory potential. This work provides an overview of the different therapeutic strategies currently being tested for NAFLD, other than, or along with, the recommendation of weight loss.

Keywords: cirrhosis; farnesoid X receptor (FXR); natural compounds; nonalcoholic fatty liver disease (NAFLD); nonalcoholic steatohepatitis (NASH); peroxisome proliferator-activated receptor (PPAR).

Figure 1

Schematic representation of NAFL/NASH pathogenesis and possible therapeutic approaches. Hepatic steatosis is the result of high diatary intake of fats and sugars together with a sedentary lifestyle. Ingested fatty acids are taken up from the circulation into the liver via CD36 and FATP transporters. Fatty acids are subsequently oxidized within the mitochondria by the β-oxidation process, stored within hepatic droplets or esterified into triglycerides to form VLDL. Insulin resistance, together with high fat consumption, can worsen the dysregulation of the lipid metabolism, leading to increased lipolysis. This kind of lipid impairment promotes oxidative stress, endoplasmic reticulum (ER) stress, and cytokines release, with the activation of Kupffer (KCs) and hepatic stellate cells (HSCs). As a consequence of the mitochondrial damage, reactive oxygen species (ROS) are produced, causing both lipid and protein peroxidation. Finally, the activation of HSCs favors the production of fibrillar collagen, leading to fibrotic scar deposition within the liver. In this complex setting, different therapeutic strategies have been developed in order to target the most significant pathways related to NAFL/NASH pathogenesis. Abbreviations: CD36: clustering domain 36; ER: endoplasmic reticulum; FATP: fatty acid transport protein; FXR: farnesoid X receptor; GLP-1: glucagon-like peptide 1; PPAR: peroxisome proliferator-activated receptor; PPRE: peroxisome proliferator responsive element; RXR: retinoid X receptor; ROS: reactive oxygen species; THR-β: thyrotropin-releasing hormone beta; VLDL: very low density lipoprotein. The image was created with the use of Servier Medical Art modified templates, licensed under a Creative Commons Attribution 3.0 Unported License (https://smart.servier.com), accessed on 1 June 2023.

Figure 2

Schematic representation of PPAR targeting in NAFLD/NASH treatment. The main agonists of PPARα, PPARγ, or drugs acting on both are reported. PPAR agonists can directly induce or impede the mRNA synthesis of specific target genes, depending on the cell type. Here, the main molecular actions on hepatocytes and macrophages are reported, along with the main outcomes. Abbreviations: ABCA1: ATP-binding cassette transporter A1; ABCG1: ATP-binding cassette subfamily G member 1; ACS: acetyl-CoA synthetase; ACOX: acyl-CoA oxidase; AP-1: activator protein 1; ApoA-I: apolipoprotein A-I; ApoA-II: apolipoprotein A-II; COX2: cyclooxygenase 2; CPT1: carnitine palmitoyltransferase 1B; DBI: diazepam-binding inhibitor, acyl-CoA-binding protein; FATP: fatty acid transport protein; IL-1: interleukin 1; NOS2: nitric oxide synthase 2; PPAR: peroxisome proliferator-activated receptor; PPRE: peroxisome proliferator response element; RXR: retinoid X receptor, STAT1: signal transducer and activator of transcription 1; TNFα: tumor necrosis factor alpha; TZDs: thiazolidinediones. The image was created with the use of Servier Medical Art modified templates, licensed under a Creative Common Attribution 3.0 Unported License (https://smart.servier.com), accessed on 1 June 2023.

Figure 3

Schematic representation of FXR signaling within the liver. FXR signaling modulates both carbohydrate and lipid metabolism through the binding with SHP promoter. Due to the interaction with SHP, FXR inhibits the expression of NTCP (not shown), thus reducing the entrance of bile acids from the circulation. The modulation of LDLR by FXR is mediated by the inhibition of PCSK9 and the activation of reverse cholesterol transport (ABCG5/8). The activation of FXR also suppresses hepatic lipogenesis, decreasing the expression of SREBP1-c. In addition, upregulating PPARα, FXR also promotes free fatty acids β-oxidation and reduced VLDL production by the downregulation of MTP enzyme. Moreover, FXR acts at intestinal level, with the release of FGF19/15, which in turn bind to FGFR4 on the surfaces of hepatocytes, leading to the inhibition of CYP7A1 and CYP8B1. FXR activation is linked to the activation of SR-BI in the liver, reducing HDL plasma levels, consistent with the reduced synthesis of APO-AI. Abbreviations: ABCG5: ATP-binding cassette type 5; ABCG8: ATP-binding cassette type 8; APOA1: apolipoprotein A-I; APOB: apolipoprotein B; BAs: bile acids; CYP7A1: cytochrome P450 family 7 subfamily A member 1; CYP8B1: cytochrome P450 family 8 subfamily B member 1; FGF19: fibroblast growth factor 19; FGFR4: fibroblast growth factor receptor 4; FXR: farnesoid X receptor; GSK: glycogen synthase kinase; HDL: high-density lipoprotein; LDL: low-density lipoprotein; LDLR: low-density lipoprotein receptor; LXR: liver X receptor; MTP: microsomal triglyceride transfer protein; NTCP: Na⁺ taurocholate cotransporting polypeptide; PEPCK: phosphoenolpyruvate carboxy kinase; PCSK9: proprotein convertase subtilisin/kexin type 9; PPAR-α: peroxisome proliferator-activated receptor alpha; SHP: small heterodimer partner 1; SR-BI: scavenger receptor class B, type I; SREBP-1c: sterol regulatory element-binding protein 1; TG: triglycerides; VLDL: very low density lipoprotein. The image was created with the use of Servier Medical Art modified templates, licensed under a Creative Common Attribution 3.0 Unported License (https://smart.servier.com), accessed on 1 June 2023.