Insights into the Epidemiology, Pathogenesis, and Therapeutics of Nonalcoholic Fatty Liver Diseases

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease which affects ≈25% of the adult population worldwide, placing a tremendous burden on human health. The disease spectrum ranges from simple steatosis to steatohepatitis, fibrosis, and ultimately, cirrhosis and carcinoma, which are becoming leading reasons for liver transplantation. NAFLD is a complex multifactorial disease involving myriad genetic, metabolic, and environmental factors; it is closely associated with insulin resistance, metabolic syndrome, obesity, diabetes, and many other diseases. Over the past few decades, countless studies focusing on the investigation of noninvasive diagnosis, pathogenesis, and therapeutics have revealed different aspects of the mechanism and progression of NAFLD. However, effective pharmaceuticals are still in development. Here, the current epidemiology, diagnosis, animal models, pathogenesis, and treatment strategies for NAFLD are comprehensively reviewed, emphasizing the outstanding breakthroughs in the above fields and promising medications in and beyond phase II.

Keywords: diagnosis; epidemiology; nonalcoholic fatty liver disease (NAFLD); pathogenesis; treatments.

Figure 1

Risk factors of NAFLD. NAFLD is a complex and multifactorial disease; myriad of factors including environmental factors, gut microbiota, insulin resistance, obesity, as well as genetic and epigenetic factors are all implicated in the pathogenesis of the disease. HFD, high‐fat diet.

Figure 2

Signaling involved in the inflammation, metabolism, cell death, and fibrogenesis process of NAFLD. DAMP, danger‐associated molecular patterns; PAMP, pathogen‐associated molecular patterns; TLRs, Toll‐like receptors; RAGE, receptor for advanced glycation end‐products; SR, scavenger receptor; TIRAP, TIR domain‐containing adaptor protein; TRAM, TRIF‐related adaptor molecule; MyD88, myeloid differentiation factor 88; TRIF, TIR‐domain‐containing adaptor‐inducing interferon‐β; MAPK, mitogen‐activated protein kinase; JNK, Jun N‐terminal kinase; ERK, extracellular signal‐regulated kinase; IRF, interferon regulatory factor; MKK, MAPK kinase; ASK1, apoptosis signal‐regulating kinase 1; TAK1, TGFβ‐activated kinase 1; PPAR, peroxisome proliferator‐activated receptors; AMPK, 5′ adenosine monophosphate‐activated protein kinase; IFN, interferon; ER, endoplasmic reticulum; FFA, free fatty acids; ROS, reactive oxygen species; TCA, tricarboxylic acid cycle; PERK, protein kinase R‐like ER kinase; XBP1, X‐box‐binding protein 1; TNF, tumor necrosis factor; IL, interleukin; TFs, transcription factors; PDGF, platelet‐derived growth factor; MCP‐1, monocyte chemoattractant protein‐1; MMP, matrix metalloproteinase; MLKL, mixed lineage kinase domain‐like protein; RIPK, receptor‐interacting proteins kinase; MPT, mitochondrial permeability transition.