Pathophysiology of NAFLD and NASH in Experimental Models: The Role of Food Intake Regulating Peptides

Abstract

Obesity, diabetes, insulin resistance, sedentary lifestyle, and Western diet are the key factors underlying non-alcoholic fatty liver disease (NAFLD), one of the most common liver diseases in developed countries. In many cases, NAFLD further progresses to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and to hepatocellular carcinoma. The hepatic lipotoxicity and non-liver factors, such as adipose tissue inflammation and gastrointestinal imbalances were linked to evolution of NAFLD. Nowadays, the degree of adipose tissue inflammation was shown to directly correlate with the severity of NAFLD. Consumption of higher caloric intake is increasingly emerging as a fuel of metabolic inflammation not only in obesity-related disorders but also NAFLD. However, multiple causes of NAFLD are the reason why the mechanisms of NAFLD progression to NASH are still not well understood. In this review, we explore the role of food intake regulating peptides in NAFLD and NASH mouse models. Leptin, an anorexigenic peptide, is involved in hepatic metabolism, and has an effect on NAFLD experimental models. Glucagon-like peptide-1 (GLP-1), another anorexigenic peptide, and GLP-1 receptor agonists (GLP-1R), represent potential therapeutic agents to prevent NAFLD progression to NASH. On the other hand, the deletion of ghrelin, an orexigenic peptide, prevents age-associated hepatic steatosis in mice. Because of the increasing incidence of NAFLD and NASH worldwide, the selection of appropriate animal models is important to clarify aspects of pathogenesis and progression in this field.

Comprehensive analysis of LncRNAs expression profiles in an in vitro model of steatosis treated with Exendin-4

“…Interestingly, some of the signaling pathways above were associated with the effect of the GLP-1R agonist liraglutide on NAFLD [ 55 ]. Further studies are warranted to unravel how all these signaling pathways' combined effect leads to improvement of steatosis upon treatment with GLP-1R agonists.…”

“…Furthermore, a number of signaling pathways previously implicated in different stages of NAFLD were also identified, including the signaling pathways of Wnt [38], insulin [49]; mTOR [26], TGF-β [50], NOD [51], TOLL-like receptor [52], VEGF [53], and PPARs [54]. Interestingly, some of the signaling pathways above were associated with the effect of the GLP-1R agonist liraglutide on NAFLD [55]. Further studies are warranted to unravel how all these signaling pathways' combined effect leads to improvement of steatosis upon treatment with GLP-1R agonists.…”

Emerging Treatment Options for Sarcopenia in Chronic Liver Disease

“…In particular, NASH is characterized by hepatic steatosis, inflammation, and liver cell damage [ 71 ]. In addition to chronic inflammation, which is currently observed to have a direct relationship with the severity of NAFLD, insulin resistance and physical inactivity are important risk factors that are related to the development of both sarcopenia and NAFLD [ 11 , 72 ]. Hepatic lipotoxicity and non-liver factors, such as inflammation in adipose tissues, are linked to the elevation of proinflammatory cytokines and chemokines as key markers of NASH, such as tumor necrosis factor α (TNF-α), IL-6, chemokine CC ligand-2, and C-reactive protein [ 72 , 73 , 74 ].…”

“…In addition to chronic inflammation, which is currently observed to have a direct relationship with the severity of NAFLD, insulin resistance and physical inactivity are important risk factors that are related to the development of both sarcopenia and NAFLD [ 11 , 72 ]. Hepatic lipotoxicity and non-liver factors, such as inflammation in adipose tissues, are linked to the elevation of proinflammatory cytokines and chemokines as key markers of NASH, such as tumor necrosis factor α (TNF-α), IL-6, chemokine CC ligand-2, and C-reactive protein [ 72 , 73 , 74 ]. Following adipocyte enlargement in NAFLD, macrophage recruitment and polarization in the proinflammatory state in adipose tissues increase various proinflammatory signals, such as adipokines, contributing to the progression of NAFLD [ 75 , 76 ].…”

Pengaruh Diet Tinggi Lemak dan Tinggi Fruktosa Serta Pemberian Karbon Tetraklorida Terhadap Kadar Prostate-Specific Antigen Pada Tikus

“…Telah diketahui bahwa HFHFD menyebabkan peningkatan berat badan, resistensi insulin dan hiperglikemia (15). Penelitian oleh Kohli dkk, menunjukkan bahwa diet tinggi lemak dan tinggi fruktosa berpengaruh terhadap peningkatan berat badan (16). Penelitian oleh Chheda dkk, terhadap tikus wistar jantan yang diberikan asupan HFHFD dan CCl4.…”