Metabolic tissues are exquisitely specialized for nutrient and energy handling, yet they retain a striking capacity for plasticity and reprogramming. Our research spans the fundamental biology of tissue and organismal metabolism, the discovery of novel endocrine hormones, and the role of the immune and stromal microenvironment in shaping metabolic disease progression and liver regeneration.
Metabolic liver disease and liver regeneration
Our understanding of the pathophysiological drivers of metabolic dysfunction-associated steatohepatitis (MASH), a common liver disease associated with metabolic syndrome, remains limited. Using single-cell and spatial transcriptomics, we map the landscape of liver cell heterogeneity and intercellular crosstalk across health and metabolic liver disease.
Our work dissects the mechanisms driving MASH-associated hepatocyte senescence, cellular reprogramming and liver regeneration, as well as the pathophysiological drivers of advanced MASH and end-stage liver disease, such as cirrhosis and liver cancer. We focus on clarifying the importance of restoring the balance between liver injury and regeneration for MASH resolution.
Metabolic crosstalk via secreted factors
Cells and tissues do not exist in isolation in the body; instead, they are constantly exposed to the ebb and flow of nutrients and hormones and release secreted factors that serve as metabolic signals. By discovering novel adipocyte-derived (NRG4) and hepatocyte-derived (TSKU) hormones, we reveal how a distributed endocrine network orchestrates metabolic physiology and homeostasis at the whole-organism scale.
Combining global profiling with single-cell resolution, we identify new ligand-receptor pairs, define their roles in inter-organ crosstalk and pursue their potential as biologic therapeutics for metabolic disease.
Lipid-associated macrophages in metabolic disease
Macrophages play integral roles in host defense, tissue homeostasis and disease progression. Altered macrophage polarization, characterized by distinct transcriptional and functional states, has been causally linked to metabolic disorders, including adipose dysfunction, MASH and atherosclerosis.
Lipid-associated macrophages (LAMs) are a unique macrophage population tightly linked to tissue injury across diverse disease settings and marked by high expression of effector molecules such as TREM2 and MS4A7. We investigate the pathophysiological mechanisms underlying LAM induction and function in metabolic disease progression and resolution.
In the News
- Hormone secreted by fat cells could be used to treat liver tumours, mice study shows, BBC Science Focus, Aug. 15, 2022
- Your muscles like the 'taste' of sugar, too, Mother Nature Network, May 12, 2017
- Fat hormone Nrg4 may hold key to new treatments of fatty liver disease: study, Xinhua News, Nov. 8, 2017
- Lifting Weights Can Control Blood Sugar, Time, April 10, 2013
Journal Covers
Molecular Cell, May 4, 2017
"On the cover: Skeletal muscle senses blood sugar levels and engages a nutrient signaling cascade to maintain glucose homeostasis. In this issue of Molecular Cell, Meng et al. (pp. 332–344) discovered a glucose sensing pathway in skeletal myocytes that promotes muscle glucose disposal through insulin-independent AKT activation. This pathway is engaged by the sulfonylurea class of anti-diabetic drugs and contributes to their glucose-lowering effects. This study illustrates the concerted action of hormonal (insulin) and nutrient (glucose) signaling in skeletal muscle in systemic glucose homeostasis. Artwork by Stephanie King."
Journal of Clinical Investigation, Dec. 1, 2017
"In this issue of the JCI, Guo et al. demonstrate a critical role for NRG4, an adipose tissue-derived endocrine factor, in gating the transition from hepatic steatosis to nonalcoholic steatohepatitis (NASH). NRG4 signaling in hepatocytes protects against cell death and symptoms of NASH, including liver injury, inflammation, and fibrosis. The cover image depicts adipose tissue, the source of NRG4, with lipid droplets indicated in green and cell membranes in red. Image credit: Guo-Xiao Wang and Stephanie King."