Abstract：Citrin Deficiency (CD) is caused by inactivation of SLC25A13, a mitochondrial membrane protein required to move electrons from cytosolic NADH to the mitochondrial matrix in hepatocytes. People with CD do not like sweets. We discovered that SLC25A13 loss causes accumulation of glycerol-3-phosphate (G3P), which activates carbohydrate response element binding protein (ChREBP) to transcribe FGF21, which acts in the brain to restrain intake of sweets and alcohol, and to transcribe key genes of de novo lipogenesis. Mouse and human data establish G3P-ChREBP as a new mechanistic component of the Randle Cycle that contributes to metabolic dysfunction-associated steatotic liver disease (MASLD) and forms part of a system that communicates metabolic states from liver to brain in a manner that alters food and alcohol choices. The data provide a framework for understanding FGF21 induction in varied conditions, suggest ways to develop FGF21-inducing drugs, and drug candidates for both lean MASLD and support of urea cycle function in CD.

Biography：Charles Brenner is the Alfred E Mann Family Foundation Chair in Diabetes and Cancer Metabolism at the Beckman Research Institute of City of Hope in Los Angeles. Brenner, originally from Boston, completed his bachelor’s degree at Wesleyan University before moving to San Francisco to work in biotechnology. As a graduate student with Robert Fuller at Stanford, he was the first to purify and characterize Kex2 protease, the prototypical member of the PCSK family of prohormone processing proteases. He then moved back to Boston to learn X-ray crystallography as a post-doctoral fellow with Gregory Petsko and Dagmar Ringe at Brandeis, discovering that histidine triad proteins are a superfamily of nucleotide-binding proteins. Brenner established his independent research group at Thomas Jefferson University in 1996 before being recruited to Dartmouth College in 2003 and to the University of Iowa as the Roy J. Carver Chair head of biochemistry in 2009. During this time, Brenner made multiple contributions to biomedicine including defining the three dimensional structure and catalytic mechanism of the nitrilase superfamily, identifying small molecule and macromolecular inhibitors of DNA methyltransferase 1, and discovering the role of TET1 repression in KRAS-directed tumor suppressor gene hypermethylation. During this period, Brenner also became the leading global researcher in NAD metabolism, discovering the molecular basis for glutamine-dependence of eukaryotic NAD synthetases, discovering the eukaryotic nicotinamide riboside (NR) kinase pathway, establishing the technology of quantitative targeted NAD metabolomics. Brenner used this technology to show that the NAD system is disturbed in alcoholism, fatty liver, type 2 diabetes, diabetic and chemotherapeutic neuropathy, central brain injury, heart failure, postpartum, coronavirus infection and some types of cancer. Brenner’s work has been translationally important. His discovering of NR as a vitamin and work showing the induction of NR kinase genes in conditions of metabolic stress paved the way for the establishment and growth of the NAD-boosting industry. Through his leadership, more than 100 randomized clinical trials for Niagen NR have been registered, at least 8 of which showed activity as an anti-inflammatory agent with additional positive indications in neurodegenerative diseases and age-associated conditions. He is also involved in development of NAD-targeted cancer therapeutics linked to diagnostics that will guide patient selection in order to maximize safety and efficacy. In 2020, Brenner was recruited to City of Hope to establish a metabolism-focused department at the interface of diabetes and cancer. He responded to this challenge by establishing a research program on Citrin Deficiency (CD), one of the most common monogenic diseases in the world. His new work on CD establishes a glycerol-3-phosphate activation mechanism for the carbohydrate response element binding protein (ChREBP) transcription factor to explain the lean MASLD presentation of CD and as a unified framework to understand induction of the FGF21 hepatokine. Brenner is a devoted mentor of dozens of successful researchers around the world and an important public intellectual who argues for truth in science and opposes hype, particularly with respect to hype about aging research.