Abstract
Aim Nonalcoholic steatohepatitis (NASH) is the consequence of insulin resistance, fatty acid accumulation, oxidative stress, and lipotoxicity. We hypothesize that an increase in the inflammatory adipokine NOV decreases antioxidant Heme Oxygenase 1 (HO-1) levels in adipose and hepatic tissue, resulting in the development of NASH in obese mice. Methods Mice were fed a high fat diet (HFD) and obese animals were administered an HO-1 inducer with or without an inhibitor of HO activity to examine levels of adipose-derived NOV and possible links between increased synthesis of inflammatory adipokines and hepatic pathology. Results NASH mice displayed decreased HO-1 levels and HO activity, increased levels of hepatic heme, NOV, MMP2, hepcidin, and increased NAS scores and hepatic fibrosis. Increased HO-1 levels are associated with a decrease in NOV, improved hepatic NAS score, ameliorated fibrosis, and increases in mitochondrial integrity and insulin receptor phosphorylation. Adipose tissue function is disrupted in obesity as evidenced by an increase in proinflammatory molecules such as NOV and a decrease in adiponectin. Importantly, increased HO-1 levels are associated with a decrease of NOV, increased adiponectin levels, and increased levels of thermogenic and mitochondrial signaling associated genes in adipose tissue. Conclusions These results suggest that the metabolic abnormalities in NASH are driven by decreased levels of hepatic HO-1 that is associated with an increase in the adipose-derived proinflammatory adipokine NOV in our obese mouse model of NASH. Concurrently, induction of HO-1 provides protection against insulin resistance as seen by increased insulin receptor phosphorylation. Pharmacological increases in HO-1 associated with decreases in NOV may offer a potential therapeutic approach in preventing fibrosis, mitochondrial dysfunction, and the development of NASH.
Highlights
Metabolic syndrome and its associated pathologies of obesity, insulin resistance (IR), and dyslipidemia are often accompanied by liver involvement, defined as nonalcoholic fatty liver disease (NAFLD) [1]
We conclude that increased levels of HO-1 can prevent lipid droplet formation in the liver, preventing the development of NAFLD and nonalcoholic steatohepatitis (NASH) in obese mice
(1) The increase of the proinflammatory adipokine NOV and decrease of HO-1 in hepatic and adipose tissue of obese mice is associated with mitochondrial dysfunction and the development and progression of obesity-induced NASH. (2) Fat expansion is associated with remodeling marked by an increase in proinflammatory molecules and oxidative stress and a decrease in PGC-1α and insulin receptor phosphorylation with the eventual development of metabolic abnormalities
Summary
Metabolic syndrome and its associated pathologies of obesity, insulin resistance (IR), and dyslipidemia are often accompanied by liver involvement, defined as nonalcoholic fatty liver disease (NAFLD) [1]. Low grade inflammation due to metabolic syndrome is provoked when the capacity for adipocytes to store fat is overwhelmed resulting in the production of inflammatory cytokines leading to metabolic inflammation [3]. Increased calorie intake and obesity lead to an increase in tissue fat mass through adipocyte hyperplasia and hypertrophy, subsequently resulting in a decrease in adiponectin and an increase of inflammatory TNF-α causing IR, inflammation, and oxidative stress in the liver [5]. Steatotic livers are more sensitive to increased ROS and oxidative stress, leading to mitochondrial dysfunction, decreased levels of hepatocyte antioxidants, and inflammation, and culminating in NASH and fibrosis [8, 9]
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