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Current insights in molecular characterization of non-alcoholic fatty liver disease and treatment.

ABSTRACT: There is a continuously rising incidence of non-alcoholic fatty liver disease (NAFLD) around the world, which parallels the increasing incidence of metabolic diseases. NAFLD is a range of liver conditions that contains simple non-alcoholic fatty liver and advanced non-alcoholic steatohepatitis. In serious cases, NAFLD may develop into cirrhosis or even liver cancer. NAFLD has an intense relationship with metabolic syndrome, type 2 diabetes mellitus. It is known that gut microbiota, and functional molecules such as adenosine monophosphate-activated protein kinase JNK, and peroxisome proliferator-activated receptors (PPARs) in progressing and treating NAFLD. Traditionally, the conventional and effective therapeutic strategy is lifestyle intervention. Nowadays, new medicines targeting specific molecules, such as farnesoid X receptor, PPARs, and GLP-1 receptor, have been discovered and shown beneficial effects on patients with NAFLD. In this article, we focus on the molecular mechanisms and therapeutic approaches to NAFLD.

SUBMITTER: Che W

PROVIDER: S-EPMC9744925 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Current insights in molecular characterization of non-alcoholic fatty liver disease and treatment.

Che Wensheng W Zhao Ming M Li Xiaoqing X Li Chunlong C Cho William C WC Yu Shan S

Frontiers in endocrinology 20221129

There is a continuously rising incidence of non-alcoholic fatty liver disease (NAFLD) around the world, which parallels the increasing incidence of metabolic diseases. NAFLD is a range of liver conditions that contains simple non-alcoholic fatty liver and advanced non-alcoholic steatohepatitis. In serious cases, NAFLD may develop into cirrhosis or even liver cancer. NAFLD has an intense relationship with metabolic syndrome, type 2 diabetes mellitus. It is known that gut microbiota, and functiona ...[more]

PMID: 36523601

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Project description:One of the most common complications of childhood obesity is the non-alcoholic fatty liver disease (NAFLD), which is the most common form of liver disease in children. NAFLD is defined by hepatic fat infiltration > 5% hepatocytes, as assessed by liver biopsy, in the absence of excessive alcohol intake, viral, autoimmune and drug-induced liver disease. It encompasses a wide spectrum of liver diseases ranging from simple steatosis to non-alcoholic steatohepatitis, which, in turn, can evolve into cirrhosis and end stage liver disease. Obesity and insulin resistance are the main risk factors for pediatric NAFLD. In fact, NAFLD is strongly associated with the clinical features of insulin resistance especially the metabolic syndrome, prediabetes and type 2 diabetes mellitus (T2D). In particular, it has been clearly shown in obese youth that the prevalence of metabolic syndrome, pre-diabetes and type 2 diabetes increases with NAFLD severity progression. Evidence that not all of the obese patients develop NAFLD suggests that the disease progression is likely to depend on complex interplay between environmental factors and genetic predisposition. Recently, a non-synonymous SNP (rs738409), characterized by a C to G substitution encoding an isoleucine to methionine substitution at the amino acid position 148 in the patatin like phospholipase containing domain 3 gene (PNPLA3), has been associated with hepatic steatosis in a multiethnic cohort of adults as well as in children. Another important polymorphisms that acts with PNPLA3 to convey susceptibility to fatty liver in obese youths is the rs1260326 polymorphism in the glucokinase regulatory protein. The pharmacological approach in NAFLD children poorly adherent to or being unresponsive/partially responsive to lifestyle changes, is aimed at acting upon specific targets involved in the pathogenesis. There are some therapeutic approaches that are being studied in children. This article reviews the current knowledge regarding the pediatric fatty liver disease, the new insights and the future directions.

Project description:Liver fibrosis is the excessive expression and accumulation of extracellular matrix proteins in the liver. Fibrotic scarring occurs as the consequence of chronic injury and inflammation. While the successful treatment of hepatitis B and C reduced the burden of liver disease related to viral hepatitis, non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) are nowadays the leading causes of hepatic fibrosis worldwide. Although basic research activities have significantly advanced our understanding of the molecular disease pathogenesis, the present therapeutic options for fibrosis are still limited. In advanced disease stages, liver transplantation often remains the only curative treatment. This highlights the necessity of preventive strategies to avoid complications of fibrosis, particularly cirrhosis, portal hypertension and liver cancer. Lifestyle modifications (weight loss, exercise, healthy diet) are the basis for prevention and treatment of NAFLD-associated fibrosis. In the present review, we discuss recent advances in antifibrotic prevention and therapy. In particular, we review the current concepts for antifibrotic drug candidates in the treatment of NAFLD and NASH. While some compounds aim at reverting pathogenic liver metabolism, an alternative approach is to disconnect the injury (e.g., NAFLD) from inflammation and/or fibrosis. Investigational drugs typically target metabolic pathways, insulin resistance, hepatocyte death, inflammatory cell recruitment or activation, the gut-liver axis, matrix expression or matrix turnover. While several promising drug candidates failed in phase 2 or 3 clinical trials (including elafibranor, emricasan and selonsertib), promising results with the farnesoid X receptor agonist obeticholic acid, the pan-PPAR agonist lanifibranor and the chemokine receptor CCR2/CCR5 inhibitor cenicriviroc support the expectation of an effective pharmacological therapy for liver fibrosis in the near future. Tackling NAFLD-associated fibrosis from different directions by combinatorial drug treatment and effective lifestyle changes hold the greatest prospects.

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Current insights in molecular characterization of non-alcoholic fatty liver disease and treatment.

Publications

Current insights in molecular characterization of non-alcoholic fatty liver disease and treatment.

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