Metabolomics Approaches for NASH and NAFLD R&D
Nonalcoholic fatty liver disease (NAFLD) is a condition in which fat builds up in the liver. Nonalcoholic steatohepatitis (NASH) is a type of NAFLD, and if you have NASH, you have inflammation and liver cell damage, along with fat in your liver. With an estimated 60 to 80 percent of the obese population suffering from fatty liver disease, NASH and NAFLD range across a spectrum of severity, with the worst cases frequently leading to the most common type of liver cancer: hepatocellular carcinoma.
Currently, there are no treatments approved by the U.S. Federal Drug Administration (FDA), leaving liver biopsy as the "gold standard" diagnostic and liver transplantation as the only remedy for treating these diseases.
"The use of human cohorts allows us to compare and contrast the metabolic signature to the preclinical models, which helps identify similarities," said Kari Wong, PhD, a senior study director at Metabolon. "This can be helpful in the identification of biomarkers or even mechanism and natural history of disease."
The role of metabolomics in the study of NAFLD and NASH is instrumental in the identification and assessment of metabolites. Metabolites have been used throughout history 1) as a method of assessing health, 2) aiding in the understanding of tissue function throughout the 20th century, and 3) are used in present-day clinical settings where metabolites, such as glucose and cholesterol, provide insight into an individual's current health.
Dysfunctional metabolism lies at the center of NASH/NAFLD and includes lipid metabolism, cholesterol metabolism, inflammation, redox status and mitochondrial function, which can be assessed via metabolic screening.
As a global leader in metabolomics, Metabolon uses its proprietary Precision Metabolomics™ technology to provide a more holistic approach due to the ability to screen for thousands of metabolites in just one biological sample. The significance of this approach is apparent in the success experienced during Gilead's utilization of metabolomics in its experiments using an acetyl CoA carboxylase inhibitor in a well-established animal model.
Hurdles to studying NASH
An unclear collection of risk factors, complicated by multiple molecular pathways, are involved in the progression of NASH. These risk factors include external inputs like diet, lifestyle, and environment, as well as others including genetic factors, family history and ethnicity. The molecular pathways involved include derangement in lipid metabolism, alteration in oxidative stress, changes in microbiome metabolism and inflammation.
Other hurdles include a lack of robust preclinical models generated by manipulating genes and diet either alone or in combination. The translatability of these models also remains in question.
The use of metabolomics in Gilead's study of NASH/NAFLD in animal models
Gilead's use of metabolomics provides a good example of how preclinical research can be applied in the study of NASH. Using two different mouse models Gilead has been able to investigate steatosis and fibrosis separately with the intention of understanding both the mechanism of disease as well as candidate treatments.
During a recent webinar on metabolomics, Jamie Bates, PhD, research scientist at Gilead Sciences, said, "Our strategy on the preclinical side, is to evaluate mechanisms in these two animal models and also understand the mechanism of action a little bit better with metabolomics and transcriptomics."
The preclinical studies featured a model of mice treated with fast food diets and then treated for five to six months with liver-targeted acetyl CoA carboxylase inhibitor (ACCi) -- an essential enzyme in de novo lipogenesis (DNL). The control group was age matched and fed a normal chow (lean) diet.
Overall findings showed that inhibition of ACCi allowed for hepatic steatosis, while improving the function of mitochondria within the cell and reducing redox stress. These findings showed that the fast food diet induced hepatic steatosis which was at least partially rescued by treatment with ACCi. In addition, levels of membrane phospholipids, including phosphatidylethanolamine (PE) and phosphatidylcholine (PC), were reduced in the NASH group (consistent with NAFLD and NASH patients ), and both PEs and PCs were reduced in the fast food diet model and increased upon ACCi treatment.
Metabolomics gives us valuable methods to compare preclinical model trials to human models of NASH. More study is needed, but metabolomics may one day prove to outperform more invasive methods of assessing liver fibrosis, revealing opportunities to incorporate metabolomics into diagnostic tools.
 Puri P et al, Hepatology 2007 46:1081