Obesity, Diabetes and Non-Alcoholic Fatty Liver Disease – A Triangular Misery

PBC News:  Obesity, diabetes and non-alcoholic fatty liver disease are very closely linked to each other in multiple ways. Metabolic diseases like obesity, insulin resistance (IR), type 2 diabetes mellitus (T2DM), dyslipidaemia, and non-alcoholic fatty liver disease (NAFLD) are connected through molecular-biochemical, and complex immune mechanism. Recent studies noted that individuals with diagnosed NAFLD have a twofold increased risk of T2DM, higher risk to develop oncologic, cardiovascular , and renal disease especially when is associated with T2DM.

By now, TD2M is reported to affect 1 in 11 adults and up to 463 million people worldwide. Currently, NAFLD remains one of the most frequent liver diseases, affecting up to 25% of the general adult population and the increased incidence in children in recent years are matter of concern. In near future, it may become the most common indication for liver transplant. This scenario could derive from an unhealthy lifestyle, obesity, dyslipidaemia, type 2 diabetes mellitus, and/or relating other metabolic syndromes. It is characterized by a wide spectrum of liver diseases that vary from simple fat accumulation (benign steatosis), to inflammation (nonalcoholic steatohepatitis (NASH)), fibrosis, cirrhosis, liver failure, and finally to hepatocellular carcinoma (HCC), in the absence of excessive alcohol consumption, medications, or viral aetiology.

Illustration: NAFLD, IR, and T2DM complex immunopathogenesis. T2DM: type 2 diabetes mellitus; NAFLD: nonalcoholic fatty liver disease; NASH: nonalcoholic steatohepatitis; HCC: hepatocellular carcinoma; IR: insulin resistance; FFAs: free fatty acids; TG: triglyceride; ChREBP: carbohydrate response element-binding protein; SREBP1c: sterol regulating element-binding protein 1c; DAG: diacylglycerols; ROS: high reactive oxygen species; (Source: Journal of Diabetes Research, Volume 2020)

Bile acid signaling in metabolic disease, therapeutics and our current research

Our lab is currently focusing on investigating bile acid signaling pathways and their functions to better understand the liver metabolism, non-alcoholic fatty liver disease, obesity and insulin resistance that could lead to future possible treatment. Fundamental research in bile acid metabolism and signaling in the last couple of decades has unveiled a pioneer role for bile acids in integration of hepatic lipid, glucose, and energy metabolism. Bile acid synthesis is an important pathway for catabolism of cholesterol and is tightly regulated by a complex but integrated network of mechanisms that are not completely understood.

Recent research in mouse models and human patient studies has revealed that bile acids are signaling molecules that activate several bile acid receptors to regulate not only the classic bile acid synthesis pathway but also the alternative bile acid synthesis pathways to maintain lipid, glucose, and energy metabolism in the liver, intestine, and adipose tissue. Alteration of bile acid homeostasis affects hepatic metabolic homeostasis, causes inflammation, and contributes to the pathogenesis of metabolic diseases such as nonalcoholic fatty liver disease (NAFLD), diabetes, obesity, and inflammatory bowel diseases (IBDs).

Illutration: The gut-to-liver axis and circadian rhythms in bile acid metabolism. Bile acids control the gut microbiota population, and gut bacteria regulate bile acid metabolism, bile acid composition, and enterohepatic circulation of bile acids. Sleep disruption, high-fat diet (HFD), alcohol, and drugs alter the central clock in the hypothalamic suprachiasmatic nucleus (SCN) of the brain to desynchronize the peripheral clocks in the liver and intestine. Disruption of circadian rhythms alters bile acid homeostasis, causes liver and intestine inflammation and dysbiosis, and contributes to cholestatic liver injury, nonalcoholic fatty liver disease (NAFLD), diabetes, and inflammatory bowel diseases. (Source: Gene Expression, vol.18 and Pharmacological Reviews, 2014, 66 (4))

Progress in translation of basic research in bile acid metabolism to clinical applications for patient treatment and drug therapies for liver diseases and diabetes has been made in recent years. Bile acids and their derivatives have the unwanted side effect of pruritus, which may cause low patient compliance. Nonbile acid–based agonists specific for FXR and TGR5 may be developed for treating NAFLD and IBD. miRNA therapy has great potential for treating liver-related diseases. Current research in bile acid metabolism relies on genetically modified mouse models. Future research using proteomics, metabolomics, lipidomics, and metagenomics sequencing will identify biomarkers for diagnosis of these diseases. It is anticipated that new treatment strategies for inflammatory metabolic diseases of the digestive system will be developed.

In conclusion, we have to utter the same old proverb “prevention is better than cure”. Well maintenance of food consumption, exercise and overall a healthy lifestyle can only keep us safe from the metabolic diseases like obesity, diabetes or NAFLD. However, we are hoping to discover more ways to treat metabolic diseases by giving more efforts in research.

Writer:

Mohammad Nazmul Hasan, Ph.D.

Postdoctoral Research Fellow

Harold Hamm Diabetes Center

The University of Oklahoma Health Sciences Center

Oklahoma, USA

Email: [email protected]