Highlights d Heterogeneity and plasticity of non-parenchymal cells in healthy and NASH liver d Landscape of intrahepatic ligand-receptor signaling at single-cell resolution d Emergence of Trem2+ NASH-associated macrophages (NAMs) in mouse and human NASH d Stellakine secretion and contractile response to vasoactive hormones by HSCs

ObjectiveNonalcoholic steatohepatitis (NASH) is closely associated with metabolic syndrome and increases the risk for end-stage liver disease, such as cirrhosis and hepatocellular carcinoma. Despite this, the molecular events that influence NASH pathogenesis remain poorly understood. The objectives of the current study are to delineate the transcriptomic and proteomic signatures of NASH liver, to identify potential pathogenic pathways and factors, and to critically assess their role in NASH pathogenesis.MethodsWe performed RNA sequencing and quantitative proteomic analyses on the livers from healthy and diet-induced NASH mice. We examined the association between plasma levels of TSK, a newly discovered hepatokine, and NASH pathologies and reversal in response to dietary switch in mice. Using TSK knockout mouse model, we determined how TSK deficiency modulates key aspects of NASH pathogenesis.ResultsRNA sequencing and quantitative proteomic analyses revealed that diet-induced NASH triggers concordant reprogramming of the liver transcriptome and proteome in mice. NASH pathogenesis is linked to elevated plasma levels of the hepatokine TSK, whereas dietary switch reverses NASH pathologies and reduces circulating TSK concentrations. Finally, TSK inactivation protects mice from diet-induced NASH and liver transcriptome remodeling.ConclusionsGlobal transcriptomic and proteomic profiling of healthy and NASH livers revealed the molecular signatures of diet-induced NASH and dysregulation of the liver secretome. Our study illustrates a novel pathogenic mechanism through which elevated TSK in circulation promotes NASH pathologies, thereby revealing a potential target for therapeutic intervention.

Hepatic lipogenesis is aberrantly induced in nonalcoholic fatty liver disease (NAFLD) via activation of the LXR-SREBP1c pathway. To date, a number of protein factors impinging on the transcriptional activity of LXR and SREBP1c have been elucidated. However, whether this regulatory axis interfaces with long noncoding RNAs (lncRNAs) remains largely unexplored. Here we show that hepatic expression of the lncRNA Blnc1 is strongly elevated in obesity and NAFLD in mice. Blnc1 is required for the induction of SREBP1c and hepatic lipogenic genes in response to LXR activation. Liver-specific inactivation of Blnc1 abrogates high-fat diet-induced hepatic steatosis and insulin resistance and protects mice from diet-induced nonalcoholic steatohepatitis. Proteomic analysis of the Blnc1 ribonucleoprotein complex identified EDF1 as a component of the LXR transcriptional complex that acts in concert with Blnc1 to activate the lipogenic gene program. These findings illustrate a lncRNA transcriptional checkpoint that licenses excess hepatic lipogenesis to exacerbate insulin resistance and NAFLD.

Brown and beige adipocytes convert chemical energy into heat through uncoupled respiration to defend against cold stress. Beyond thermogenesis, brown and beige fats engage other metabolic tissues via secreted factors to influence systemic energy metabolism. How the protein and long noncoding RNA (lncRNA) regulatory networks act in concert to regulate key aspects of thermogenic adipocyte biology remains largely unknown. Here we developed a genome-wide functional screen to interrogate the transcription factors and cofactors in thermogenic gene activation and identified zinc finger and BTB domain-containing 7b (Zbtb7b) as a potent driver of brown fat development and thermogenesis and cold-induced beige fat formation. Zbtb7b is required for activation of the thermogenic gene program in brown and beige adipocytes. Genetic ablation of Zbtb7b impaired cold-induced transcriptional remodeling in brown fat, rendering mice sensitive to cold temperature, and diminished browning of inguinal white fat. Proteomic analysis revealed a mechanistic link between Zbtb7b and the lncRNA regulatory pathway through which Zbtb7b recruits the brown fat lncRNA 1 (Blnc1)/heterogeneous nuclear ribonucleoprotein U (hnRNPU) ribonucleoprotein complex to activate thermogenic gene expression in adipocytes. These findings illustrate the emerging concept of a protein-lncRNA regulatory network in the control of adipose tissue biology and energy metabolism.

Metallic-state gold nanorods are well known to exhibit strong longitudinal plasmon excitations in the near-infrared region (NIR) suitable for photothermal conversion. However, when the size decreases below ∼2 nm, Au nanostructures become nonmetallic, and whether the longitudinal excitation in plasmonic nanorods can be inherited is unknown. Here, we report atomically precise rod-shaped Au 42 (SCH 2 Ph) 32 with a hexagonal-close-packed Au 20 kernel of aspect ratio as high as 6.2, which exhibits an intense absorption at 815 nm with a high molar absorption coefficient of 1.4 × 10 5 M −1 cm −1 . Compared to other rod-shaped nanoclusters, Au 42 possesses a much more effective photothermal conversion with a large temperature increase of ∼27 °C within 5 min (λ ex = 808 nm, 1 W cm −2 ) at an ultralow concentration of 50 μg mL −1 in toluene. Density functional theory calculations show that the NIR transition is mainly along the long axis of the Au 20 kernel in Au 42 , i.e., a longitudinal excitonic oscillation, akin to the longitudinal plasmon in metallic-state nanorods. Transient absorption spectroscopy reveals that the fast decay in Au 42 is similar to that of shorter-aspect-ratio nanorods but is followed by an additional slow decay with a long lifetime of 2400 ns for the Au 42 nanorod. This work provides the first case that an intense longitudinal excitation is obtained in molecular-like nanorods, which can be used as photothermal converters and hold potential in biomedical therapy, photoacoustic imaging, and photocatalysis.