Leveraging adaptive hepatic glucose fasting responses against cardiometabolic disease
Brian DeBosch, M.D., Ph.D.
Project Summary and Progress Report:
One in every four deaths in the United States is due to cardiovascular disease. The long-term goal of our laboratory is to define new therapies against cardiac disease and its underlying causes, such as diabetes, obesity, and non-alcoholic fatty liver disease. We intend to achieve this by studying the detailed pathways that hurt or protect the heart, then design drugs that modulate these pathways to extend healthspan and lifespan. Recent data indicate that intermittent fasting and caloric restriction can prevent the abnormal heart remodeling and dysfunction that occurs after cardiac insults, such as ischemia (e.g., heart attack) or pressure overload (high blood pressure). Because sustaining a calorie-restricted or intermittent fasting diet is often difficult in real-world clinical settings, we seek to identify drugs that mimic the body’s fasting responses. We discovered a naturally-occurring sugar, trehalose, which prevents other sugars from accessing the liver, ultimately mimicking the liver’s natural glucose fasting-response. Astonishingly, we found that treating mice with trehalose prevented them from developing heart failure in response to pressure overload, just as if they had been subjected to fasting. Based on these observations, the objective for this proposal is to answer two critical questions: 1) How does the liver communicate the glucose fasting response to the heart to protect it from heart failure during pressure overload? 2) Are there other heart disease contexts in which the liver’s fasting response can protect from heart failure and abnormal heart growth, such as ischemic (heart attack) or chronic stress-hormone exposure?
We completed the experiments outlined in the original Aim 1. We found that hepatocyte TFEB (Aim 1) is necessary and sufficient for the cardioprotective effects of trehalose. To our surprise, however, hepatocyte FGF21 is dispensable for trehalose to protect against cardiac hypertrophy and LVD. (Data from Aim 1 are submitted and are in external peer review at J Clin Invest.) We addressed feasibility for the originally proposed Aim 2, “Define pathological contexts in which trehalose prevents LVH and LVD.” We showed that the hepatic fasting response attenuates pathological remodeling and LVD in an ischemic heart failure model. Specifically, we optimized and validated use of the experimental heart failure (HF) model, which entails transverse aortic constriction and a small LV apical infarction (28). In Year 2, we now will interrogate trehalose efficacy to attenuate LVH and LVD in the setting of humoral (chronic Angiotensin II [AngII] infusion-based model) and acute myocardial infarction models of disease to complete Aim 2.