Pathogenesis and treatment of non-alcoholic steatohepatitis and its fibrosis

Abstract

The initial presentation of non-alcoholic steatohepatitis (NASH) is hepatic steatosis. The dysfunction of lipid metabolism within hepatocytes caused by genetic factors, diet, and insulin resistance causes lipid accumulation. Lipotoxicity, oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum stress would further contribute to hepatocyte injury and death, leading to inflammation and immune dysfunction in the liver. During the healing process, the accumulation of an excessive amount of fibrosis might occur while healing.During the development of NASH and liver fibrosis, the gut-liver axis, adipose-liver axis, and renin-angiotensin system (RAS) may be dysregulated and impaired. Translocation of bacteria or its end-products entering the liver could activate hepatocytes, Kupffer cells, and hepatic stellate cells, exacerbating hepatic steatosis, inflammation, and fibrosis. Bile acids regulate glucose and lipid metabolism through Farnesoid X receptors in the liver and intestine.Increased adipose tissue-derived non-esterified fatty acids would aggravate hepatic steatosis.Increased leptin also plays a role in hepatic fibrogenesis, and decreased adiponectin may contribute to hepatic insulin resistance. Moreover, dysregulation of peroxisome proliferatoractivated receptors in the liver, adipose, and muscle tissues may impair lipid metabolism.Moreover, the RAS may contribute to hepatic fatty acid metabolism, inflammation, and fibrosis.The treatment includes lifestyle modification, pharmacological therapy, and nonpharmacological therapy. Currently, weight reduction by lifestyle modification or surgery is the most effective therapy. However, vitamin E, pioglitazone, and obeticholic acid have been suggested. In this review, we will introduce some new clinical trials and experimental therapies for the treatment of NASH and related fibrosis.

Noninvasive serum biomarkers for liver fibrosis in NAFLD: current and future

“…Within that spectrum of liver disease, it is patients with F3 [ 3 ] fibrosis and F4 [ 3 ] cirrhosis who are at substantial risk of death from end-stage liver disease and liver cancer. However, the earlier stages of liver fibrosis lend themselves well to therapeutic interventions to either attenuate or ameliorate progression and potentially reverse liver damage [ 4 - 7 ]. Thus, managing patients with NAFLD necessitates identification of F1 [ 3 ] and F2 [ 3 ] stages and estimation of the risk of progression to a more advanced stage of fibrosis/cirrhosis.…”

Neuregulin 4 as a novel adipokine in energy metabolism

“…Hepatic steatosis is known to be closely linked to IR ( Lee et al, 2022 ). A study analyzed the potential of adipose tissue-derived mesenchymal stem cell (ADSC) and ADSC overexpressing Nrg4 (Nrg4-ADSC) to improve IR in HFD-induced obese mice.…”

Immunotherapy for NAFLD and NAFLD-related hepatocellular carcinoma

“…Non-alcoholic fatty liver disease (NAFLD) has reached a global prevalence of 30% and the increasing trend is ongoing ( 1 ). It involves a spectrum of diseases, including hepatic steatosis and non-alcoholic steatohepatitis (NASH) ( 2 ). NAFLD may lead to life-threatening hepatic diseases, such as liver cirrhosis and hepatocellular carcinoma (HCC), and extrahepatic diseases, such as cardiovascular disease and dementia ( 3 – 6 ).…”