Treating hepatic steatosis and fibrosis by modulating mitochondrial pyruvate metabolism

A hepatic comorbidity of metabolic syndrome, known as nonalcoholic fatty liver disease (NAFLD), is increasing in prevalence in conjunction with the pandemics of obesity and diabetes. The spectrum of NAFLD ranges from simple hepatic fat accumulation to a more severe disease termed nonalcoholic steatohepatitis (NASH), involving inflammation, hepatocyte death, and fibrosis. Importantly, NASH is linked to a much higher risk of cirrhosis, liver failure, and hepatocellular carcinoma, as well as an increased risk for nonhepatic malignancies and cardiovascular disease. Interest in the understanding of the disease processes and search for treatments for the spectrum of NAFLD-NASH has increased exponentially, but there are no approved pharmacologic therapies. In this review, we discuss the existing literature supporting insulin-sensitizing thiazolidinedione compounds as potential drug candidates for the treatment of NASH. In addition, we put these results into new context by summarizing recent studies suggesting these compounds alter mitochondrial metabolism by binding and inhibiting the mitochondrial pyruvate carrier. Keywords: Nonalcoholic Steatohepatitis, Mitochondria, Pyruvate, Thiazolidinedion

Quantum Hall Exciton Condensation at Full Spin Polarization

Using Coulomb drag as a probe, we explore the excitonic phase transition in quantum Hall bilayers at nu=1 as a function of Zeeman energy, E_Z. The critical layer separation d/l for exciton condensation initially increases rapidly with E_Z, but then reaches a maximum and begins a gentle decline. At high E_Z, where both the excitonic phase at small d/l and the compressible phase at large d/l are fully spin polarized, we find that the width of the transition, as a function of d/l, is much larger than at small E_Z and persists in the limit of zero temperature. We discuss these results in the context of two models in which the system contains a mixture of the two fluids.Comment: 4 pages, 3 eps figure

Quantum Hall Exciton Condensation at Full Spin Polarization

Using Coulomb drag as a probe, we explore the excitonic phase transition in quantum Hall bilayers at ν_T = 1 as a function of Zeeman energy E_Z. The critical layer separation (d/ℓ)_c for exciton condensation initially increases rapidly with E_Z, but then reaches a maximum and begins a gentle decline. At high E_Z, where both the excitonic phase at small d/ℓ and the compressible phase at large d/ℓ are fully spin polarized, we find that the width of the transition, as a function of d/ℓ, is much larger than at small E_Z and persists in the limit of zero temperature. We discuss these results in the context of two models in which the system contains a mixture of the two fluids

Exciton Transport and Andreev Reflection in a Bilayer Quantum Hall System

We demonstrate that counterflowing electrical currents can move through the bulk of the excitonic quantized Hall phase found in bilayer two-dimensional electron systems (2DES) even as charged excitations cannot. These counterflowing currents are transported by neutral excitons which are emitted and absorbed at the inner and outer boundaries of an annular 2DES via Andreev reflection

Targeting hepatic glycerolipid synthesis and turnover to treat fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of metabolic abnormalities ranging from simple hepatic steatosis (accumulation of neutral lipid) to development of steatotic lesions, steatohepatitis, and cirrhosis. NAFLD is extremely prevalent in obese individuals and with the epidemic of obesity; nonalcoholic steatohepatitis (NASH) has become the most common cause of liver disease in the developed world. NASH is rapidly emerging as a prominent cause of liver failure and transplantation. Moreover, hepatic steatosis is tightly linked to risk of developing insulin resistance, diabetes, and cardiovascular disease. Abnormalities in hepatic lipid metabolism are part and parcel of the development of NAFLD and human genetic studies and work conducted in experimentally tractable systems have identified a number of enzymes involved in fat synthesis and degradation that are linked to NAFLD susceptibility as well as progression to NASH. The goal of this review is to summarize the current state of our knowledge on these pathways and focus on how they contribute to etiology of NAFLD and related metabolic diseases

PGC-1 coactivators: Inducible regulators of energy metabolism in health and disease

Members of the PPARγ coactivator-1 (PGC-1) family of transcriptional coactivators serve as inducible coregulators of nuclear receptors in the control of cellular energy metabolic pathways. This Review focuses on the biologic and physiologic functions of the PGC-1 coactivators, with particular emphasis on striated muscle, liver, and other organ systems relevant to common diseases such as diabetes and heart failure

Regulation of signaling and metabolism by lipin-mediated phosphatidic acid phosphohydrolase activity

Phosphatidic acid (PA) is a glycerophospholipid intermediate in the triglyceride synthesis pathway that has incredibly important structural functions as a component of cell membranes and dynamic effects on intracellular and intercellular signaling pathways. Although there are many pathways to synthesize and degrade PA, a family of PA phosphohydrolases (lipin family proteins) that generate diacylglycerol constitute the primary pathway for PA incorporation into triglycerides. Previously, it was believed that the pool of PA used to synthesize triglyceride was distinct, compartmentalized, and did not widely intersect with signaling pathways. However, we now know that modulating the activity of lipin 1 has profound effects on signaling in a variety of cell types. Indeed, in most tissues except adipose tissue, lipin-mediated PA phosphohydrolase activity is far from limiting for normal rates of triglyceride synthesis, but rather impacts critical signaling cascades that control cellular homeostasis. In this review, we will discuss how lipin-mediated control of PA concentrations regulates metabolism and signaling in mammalian organisms