Explore our resources by research/diagnostic specialty or content type

March 7, 2017: Lately, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) have been widely discussed in both the clinical and research communities. Some of the focus has been related to alternative research methods that can improve diagnostic and monitoring methodologies at the clinical level. These include more sophisticated imaging techniques as well as non-invasive methods such as the screening or monitoring of relevant biomarkers like adiponectin. Taking a step back and assessing the use of adiponectin in NAFLD and NASH research can have an impact at the bedside, and is important to fighting these asymptomatic, chronic, and lethal diseases.

Two projects, one led by Dr. Kenneth Cusi at the University of Florida and one led by Dr. Philipp Scherer at the University of Texas Southwestern Medical Center, are relevant to this discussion. Dr. Cusi’s group has been studying the effects of pioglitazone on the progression from NAFLD to NASH. This year, Cusi published clinical trial data demonstrating the metabolic efficacy of pioglitazone in a large population of patients with pre-diabetes, type 2 diabetes, or NASH¹. Consistent with some of their earlier work, the group found that an increase in adiponectin levels is still the best indicator of histological response to treatment. In NASH patients with a positive histological response to treatment, increased levels of adiponectin could be seen in as early as 1 to 3 months post-treatment. Levels continued to rise throughout the course of therapy.

On the contrary, as demonstrated by another study from Cusi’s group², patients receiving a placebo experienced  minimal changes, if any, in adiponectin levels, while non-responders showed decreased adiponectin levels. The crucial role of adiponectin in NAFLD and NASH research may not be surprising to the community. Studies have shown that decreased levels of adiponectin correlate to increased levels of metabolic syndrome and type 2 diabetes. Dysfunctional adipose tissue in overweight and obese individuals leads to excessive free fatty acids (FFAs) in the liver. As a result, this leads to the accumulation of triglycerides, hepatocyte lipotoxicity, inflammation, and fibrosis³. Dr. Scherer and his team have been studying the effects of pioglitazone on ceramides – molecules composed of sphingosine and fatty acid. His study⁴ also demonstrated an increase in both total and high molecular weight (HMW) adiponectin levels in samples from patients who were treated with pioglitazone. In addition, his research found that adiponectin levels were inversely correlated to those of ceramides, suggesting that ceramide metabolism and adiponectin levels are closely related. The causality of this, however, has yet to be discovered.

It is clear that the use of adiponectin in NAFLD and NASH research is becoming more and more relevant. Increased levels of the hormone have been correlated to improving histopathology of the liver, suggesting that it may play an important role in the progression from NAFLD to NASH, and perhaps even have an inhibitory and/or reversal effect. As the search continues to discover less invasive clinical solutions for the diagnosis, monitoring and treatment of NAFLD and NASH, it is important to investigate these diseases at the molecular level. Doing so will allow researchers to better understand how changes in various signaling pathways may translate to better bedside methodologies.

1. Cusi et al. (2016). Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus - A Randomized Trial. Ann Intern Med., 165(5), 305-315.
2. Bril et al. (2015). Metabolic predictors of metabolic predictors of response to pioglitazone treatment in patients with prediabetes or type 2 diabetes mellitus (T2DM) and nonalcoholic steatohepatitis (NASH). Diabetes, 64, A337.
3. Lomonaco, Chen, & Cusi. (2011). An endocrine perspective of non-alcoholic fatty liver disease (NAFLD). Ther. Adv. Endocrinol. Metab., 2(5), 211-225.
4. Warshauer et al. (2015). Effect of pioglitazone on plasma ceramides in adults with metabolic syndrome. Diabetes Metab. Res. Rev., 31, 734–744.