One of the major health problems associated with obesity is the accumulation of fat in the liver. Academic institutions and pharmaceutical companies worldwide are channeling enormous efforts to basic and clinical research in order to develop new strategies to combat obesity and its associated complications, such as NAFLD.
Obesity is a chronic disease that is now reaching epidemic proportions, with more than one-third of U.S. adults that are considered obese. It has been described as a catalyst for cardiovascular disease, type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD). The latter, a major cause of morbidity and mortality in Western societies, describes a spectrum of liver conditions ranging from ectopic
accumulation of fat in the liver (hepatic steatosis) to non-alcoholic steatohepatitis (NASH), which can be complicated by fibrosis, cirrhosis and hepatocellular carcinoma (HCC). In response to nutritional and hormonal signals, the liver regulates several features of lipid metabolism including free fatty acid (FFA) β-oxidation, de novo lipogenesis and lipoprotein uptake and secretion. Hepatic steatosis is a result of
increased hepatic lipogenesis combined with decreased FFA β-oxidation as well as increased transport of FFAs to the liver from extra-hepatic (primarily adipose) tissues.
Several lines of evidence suggest that NAFLD promotes type 2 diabetes mellitus (T2DM). While NAFLD is present in 20-30% of the general population, it reaches the impressive prevalence of 50-75% of patients affected by T2DM. Conversely, insulin resistance, which occurs in 66-83% of patients with NAFLD,
increases the FFAs flux from adipocytes to the liver, promotes hepatic lipid accumulation and liver injury. Once T2DM is fully developed, it further contributes not only to the development of steatosis, but also to NASH, fibrosis, cirrhosis and possibly HCC. To date, NAFLD is considered as a promising, new predictive marker for T2DM, with potential therapeutic implications.
Recent findings have revealed a significant role of the endocannabinoid (eCB) system in the pathogenesis of NAFLD via the regulation of both CB1 and CB2 receptors. eCBs are endogenous lipid ligands that interact with the same cannabinoid receptors
Our research aims to evaluate the antisteatotic effects of CBD. Our working hypothesis is that phytocannabinoids) could mitigate hepatic de novo lipogenesis or increase hepatic fatty acid β-oxidation to prevent the development of NAFLD.
The current research project is uniquely poised to address the therapeutic potential of phytocannabinoids in ameliorating fat accumulation in hepatocytes, as well as to define the molecular mechanisms underlying their role in the development of NAFLD. Thus, this research proposal could lead to the development and clinical testing of phytocannabinoids for the treatment of fatty liver in humans.
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