Stress-induced hepatokines in inflammation and metabolism

The liver has long been recognized as a central metabolic hub and inflammatory sentinel, yet only in the past decade has its endocrine dimension emerged with full clarity. A growing family of hepatokines, liver-derived circulating proteins, has reshaped our understanding of how hepatocytes communicate metabolic or environmental stress to peripheral organs. Among these, the recent identification of cAMP-responsive element-binding protein hepatic-specific CREBH-C, the secreted C-terminal fragment of the endoplasmic reticulum (ER)-resident transcription factor CREBH, adds a new layer to the cross-organ dialog.[1] Together with the established hepatokines, such as fibroblast growth factor 21 (FGF21), Angiopoietin-like 4 (ANGPTL4), hepassocin, and selenoprotein P,[2,3] CREBH-C underscores a unifying principle: cellular stress on the liver generates systemic signals that recalibrate whole-body metabolism and immunity. One of the most intriguing features of CREBH-C is its origin. CREBH was originally characterized for its similarity to other ER-tethered transcription factors, such as Activating Transcription Factor 6 (ATF6) and Sterol Regulatory Element-Binding Protein (SREBP), that respond to metabolic stress and are processed through regulated intramembrane proteolysis.[4,5] In this paradigm, only the liberated transcriptional domain, the N-terminus of CREBH (CREBH-N), is considered biologically active as a transcription factor.[4,6,7] The recent work upends this assumption, demonstrating that the residual C-terminal fragment of CREBH (CREBH-C) is not inert but rather actively secreted, in a process under the regulation of Calcium/Calmodulin-dependent protein kinase II (CaMKII)-dependent phosphorylation.[1] Once in circulation, CREBH-C directly disrupts the ANGPTL3–ANGPTL8 complex, a potent inhibitor of lipoprotein lipase (LPL). By relieving this inhibition, CREBH-C amplifies LPL activity, accelerating triglyceride hydrolysis and promoting lipid uptake by peripheral tissues.[1] This mechanism positions CREBH-C as a sensor-and-responder signal under hepatic stress. In mouse models under metabolic stress conditions, such as fasting or under an atherogenic diet, boosting CREBH-C improved triglyceride clearance and mitigated hepatic steatosis. Human data confirm clinical relevance, with CREBH variants linked to triglyceride elevation and cardiovascular and metabolic disorders.[1] Together, the dual signaling mode mediated by CREBH, nuclear gene regulation by the CREBH N-terminal fragment as a transcription factor and endocrine action by the C-terminal fragment as a hepatokine, illustrates a sophisticated strategy for synchronizing hepatic stress responses with systemic metabolic needs [Figure 1].Figure 1: Illustration of the pathways through which the stress hepatokine cAMP responsive element-binding protein hepatic-specific-C (CREBH-C) regulates lipoprotein lipase activity and subsequent triglyceride lipolysis and partitioning through inhibitory interactions with Angiopoietin-like 3 (ANGPTL3) and ANGPTL8. TF: Transcription factor, TG: Triglycerides, FA: Fatty acids, LPL: Lipoprotein lipase, ANGPTL3: Angiopoietin-like 3. ANGPTL8: Angiopoietin-like8CREBH-C joins a growing roster of hepatokines whose secretion is tightly linked to cellular stress. The following are a few examples of stress-induced hepatokines that are associated with CREBH. FGF21, induced by fasting, mitochondrial stress, and ER stress, promotes fatty acid oxidation, ketogenesis, and insulin sensitization.[8,9] CREBH functions as a major regulator of FGF21 production under pathophysiological conditions.[9-12] The N-terminus of CREBH, generated by regulated intramembrane proteolysis,[4] acts as a transcription factor to interact with PPARα to drive optimized expression of FGF21 from the liver in response to energy demands or liver injury-causing stimuli.[9] Treatment of recombinant FGF21 protein can reverse hypertriglyceridemia, hypoketonemia, and hepatic inflammation and improve hepatic fibrosis developed in CREBH-null mice after an atherogenic high-fat diet.[9] ANGPTL4 is a multifunctional secreted protein that is upregulated by fasting and hypoxia.[13,14] It inhibits LPL activity to prioritize lipid availability for tissues such as the heart and skeletal muscle while also modulates inflammatory pathways.[14-16] ANGPTL4-mediated inflammatory actions arise from context-dependent interactions with endothelial cells, immune cells, and lipid metabolic pathways. Cleavage of ANGPTL4 into N-terminal and C-terminal fragments yields distinct functions: the C-terminal fragment signals through integrins (α5β1, αvβ3, and αvβ5) to activate Focal Adhesion Kinase (FAK)/c-Src kinase (Src), destabilize endothelial junctions, and promote vascular leak in settings such as acute lung injury, diabetic retinopathy, and metastasis.[17-19] Conversely, ANGPTL4 can exert anti-inflammatory effects by suppressing Toll-like receptor-induced Nuclear Factor-κB (NF-κB) signaling in macrophages and by limiting lipid loading through LPL inhibition, thereby reducing foam-cell formation and metabolic inflammation.[16] ANGPTL4 expression is tightly regulated by PPARα/β/γ and transforming growth factor-β (TGF-β)/SMAD signaling, integrating nutritional, hypoxic, and inflammatory cues. In the intestine, ANGPTL4 activates cAMP–PKA to strengthen barrier integrity and restrain bacterial-driven inflammation.[20] ANGPTL4 appears to operate as a context-specific modulator that can either propagate inflammatory vascular permeability or promote resolution and tissue protection depending on tissue type, fragment form, and metabolic state. ANGPTL3 and ANGPTL4 are structurally related regulators of lipid metabolism, but they diverge markedly in their tissue distribution, activation mechanisms, and inflammatory signaling profiles.[21,22] ANGPTL3 is produced almost exclusively by the liver and functions primarily as a systemic regulator of triglyceride metabolism through LPL inhibition, especially in complex with ANGPTL8, thereby influencing inflammation indirectly by altering circulating lipoprotein levels and lipid-driven immune activation.[23,24] In contrast, ANGPTL4 is expressed in multiple tissues – including adipose tissue, intestine, and skeletal muscle, where proteolytic cleavage yields fragments with distinct functions: N-terminus of ANGPTL4 modulates local lipid uptake via LPL inhibition, whereas C-terminus of ANGPTL4 engages integrin–FAK–Src signaling to regulate endothelial permeability and leukocyte trafficking.[17] ANGPTL4 also directly interfaces with immune pathways by suppressing or activating NF-κB depending on the cellular context and by strengthening gut barrier function through cAMP–PKA signaling.[16,25] Consequently, ANGPTL3 largely shapes systemic metabolic inflammation, whereas ANGPTL4 acts as a context-dependent metabolic–immune integrator, capable of either promoting vascular inflammation or facilitating anti-inflammatory tissue protection. These examples highlight a shared theme: hepatokines integrate nutrient sensing, inflammatory cues, and cellular organelle stress to regulate systemic physiology. Unlike endocrine signals emanating from adipose tissue or muscle, hepatokines are uniquely positioned at the crossroads of inflammation and metabolism. Hepatocytes experience acute-phase responses, ER stress from lipotoxicity, cytokine exposure from portal circulation, and metabolic flux from nutrient intake. As a result, stress-induced hepatokines often exert both metabolic and immunological effects. CREBH-C, for example, emerges specifically under metabolic stress and serves to normalize lipid levels, representing an elegant countermeasure to hypertriglyceridemia, a condition that exacerbates hepatic inflammation and systemic insulin resistance. Characterization of stress-induced hepatokines strengthens a paradigm that the liver uses secreted factors to translate internal stress into systemic instruction. The hepatokines orchestrate adaptive responses that align energy distribution, immune activity, and tissue-specific substrate use with the liver’s metabolic state. As research continues to uncover new stress-induced hepatokines and clarify their roles, the field is shifting toward a unifying framework, in which hepatocyte stress, whether mitochondrial, ER-based, inflammatory, or nutritional, acts as a central coordinator of organismal homeostasis. Understanding and harnessing this network promises to reshape the treatment of metabolic syndrome, fatty liver disease, cardiovascular risk, and chronic inflammatory states. Ethical policy and institutional review board statement Not applicable. Data availability statement Data sharing is not applicable to this article as no datasets were generated and/or analyzed during the current study. Financial support and sponsorship This work is partially supported by the National Institutes of Health grant DK090313, DK126908, and DK132065. Conflicts of interest Dr. Kezhong Zhang is an Editor-in-Chief of Environmental Disease. The article was subject to the journal's standard procedures, with peer review handled independently of this Editor and their research groups.