Emerging evidence suggests that crosstalk between Kupffer cells (KCs) and hepatocytes protects against non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanisms that lead to the reduction of steatosis in NAFLD remain obscure. Ttp^+/+ and Ttp^-/- mice were fed with a high-fat diet. Hepatic steatosis was analyzed by Nile Red staining and measurement of inflammatory cytokines. Lipid accumulation and cell death were evaluated in co-culture systems with primary hepatocytes and KCs derived from either Ttp^+/+ or Ttp^-/- mice. Tristetraprolin (TTP), an mRNA binding protein, was essential for the protective effects of metformin in NAFLD. Metformin activated TTP via the AMPK-Sirt1 pathway in hepatocytes and KCs. TTP inhibited TNF-α production in KCs, which in turn decreased hepatocyte necroptosis. Downregulation of Rheb expression by TTP promoted hepatocyte lipophagy via mTORC1 inhibition and increased nuclear translocation of transcription factor-EB (TFEB). Consistently, TTP-deficient NAFLD mice failed to respond to metformin with respect to alleviation of hepatic steatosis, protection of hepatocyte necroptosis, or induction of lipophagy. TTP, which is essential for the protective effects of metformin, may represent a novel primary therapeutic target in NAFLD.

Obesity-induced hypothalamic inflammation is characterized by activation of microglia, which are resident macrophages of the central nervous system, and is implicated in the derangement of energy homeostasis, metabolic complications, and neurodegenerative diseases. Quercetin, a naturally occurring flavonoid, is known to protect against oxidative stress and inflammation-related metabolic complications. Here, we demonstrate that quercetin reduces obesity-induced hypothalamic inflammation by inhibiting microglia-mediated inflammatory responses, and the beneficial action of quercetin is associated with heme oxygenase (HO-1) induction. Quercetin markedly reduced the production of inflammatory mediators (monocyte chemoattractant protein (MCP)-1, interleukin (IL-6), IL-1β, nitric oxide) by microglia stimulated with saturated fatty acid palmitate and/or lipid-laden microglia-conditioned medium. Quercetin also upregulated the expression of HO-1 in palmitate-treated lipid-laden microglia, and the actions of quercetin against microglia activation accompanied by IκBα degradation were abolished by a HO-1 inhibitor. Moreover, quercetin supplementation reduced the levels of inflammatory cytokines and microglia activation markers in the hypothalamus of high fat diet (HFD)-fed obese mice, which was accompanied by upregulation of HO-1. These findings indicate that quercetin suppresses microglia-mediated inflammatory responses via the induction of HO-1, and hence protects against obesity-induced hypothalamic inflammation.

Endogenous carbon monoxide (CO) is produced by heme oxygenase-1 (HO)-1 which mediates the degradation of heme into CO, iron, and biliverdin. Also, CO ameliorates the human inflammatory bowel diseases and ulcerative colitis. However, the mechanism for the effect of CO on the inflammatory bowel disease has not yet been known. In this study, we showed that CO significantly increases survival percentage, body weight, colon length as well as histologic parameters in DSS-treated mice. In addition, CO inhalation significantly decreased DSS induced pro-inflammatory cytokines by inhibition of GSK-3βin mice model. To support the in vivo observation, TNF-α, iNOS and IL-10 after CO and LiCl treatment were measured in mesenteric lymph node cells (MLNs) and bone marrow-derived macrophages (BMMs) from DSS treated mice. In addition, we determined that CO potentially inhibited GSK-3βactivation and decreased TNF-αand iNOS expression by inhibition of NF-κB activation in LPS-stimulated U937 and MLN cells pretreated with CO. Together, our findings indicate that CO attenuates DSS-induced colitis via inhibition of GSK-3βsignaling in vitro and in vivo. Importantly, this is the first report that investigated the molecular mechanisms mediated the novel effects of CO via inhibition GSK-3βin DSS-induced colitis model.

The translocation of transcription factor EB (TFEB) to the nucleus plays a pivotal role in the regulation of basic cellular processes, such as lysosome biogenesis and autophagy. Autophagy is an intracellular degradation system that delivers cytoplasmic constituents to the lysosome, which is important in maintaining cellular homeostasis during environmental stress. Furthermore, oxidative stress is a critical cause for the progression of neurodegenerative diseases. Curcumin has anti-oxidative and anti-inflammatory activities, and is expected to have potential therapeutic effects in various diseases. In this study, we demonstrated that curcumin regulated TFEB export signaling via inhibition of glycogen synthase kinase-3β (GSK-3β); GSK-3β was inactivated by curcumin, leading to reduced phosphorylation of TFEB. We further showed that H₂O₂-induced oxidative stress was reduced by curcumin via the Nrf2/HO-1 pathway in human neuroblastoma cells. In addition, we showed that curcumin induced the degradation of amyloidogenic proteins, including amyloid-β precursor protein and α-synuclein, through the TFEB-autophagy/lysosomal pathway. In conclusion, curcumin regulates autophagy by controlling TFEB through the inhibition of GSK-3β, and increases antioxidant gene expression in human neuroblastoma cells. These results contribute to the development of novel cellular therapies for neurodegenerative diseases.

Acetaminophen (APAP) is widely used as an antifebrile and analgesic drug at recommended doses, whereas an overdose of APAP can cause severe liver damage. The molecular mechanisms underlying APAP‐induced liver damage remain incompletely understood. Carbon monoxide (CO), an end‐product of heme oxygenase (HO)‐1 activity, can confer anti‐inflammatory and antiapoptotic properties in cellular models of toxicity via regulation of mitochondrial function. The objective of this study was to evaluate the effects of CO on APAP‐induced hepatotoxicity and CO's relationship to regulation of endoplasmic reticulum (ER) stress and mitochondrial signaling using CO‐releasing molecules or low concentrations of CO applied as pretreatment or post‐treatment. Using genetic deletion or knockdown approaches in alpha mouse liver cells or primary hepatocytes, respectively, we investigated the role of HO‐1 and the mitophagy regulator protein Parkin on APAP‐induced expression of the ER stress‐associated apoptosis regulator cytosine‐cytosine‐adenosine‐adenosine‐thymidine (CCAAT)/enhancer‐binding protein homologous protein (CHOP). We found that CO induced Parkin expression in hepatocytes via the protein kinase RNA‐like ER kinase/eukaryotic translation initiation factor 2‐α/activating transcription factor‐4 signaling pathway. Additionally, CO gas inhalation significantly alleviated APAP‐induced liver damage in vivo and correspondingly reduced serum alanine aminotransferase and aspartate aminotransferase levels as well as proinflammatory cytokines and reduced the expression of CHOP in liver tissues while dramatically increasing hepatic HO‐1 and Parkin expression. We found that the protective effects of CO on APAP‐induced liver damage were mediated by down‐regulation of CHOP at a transcriptional and post‐translational level via induction of HO‐1 and Parkin, respectively, and associated with decreases in reactive oxygen species production and JNK phosphorylation. We conclude that CO may represent a promising therapeutic agent for APAP‐induced liver injury.—Chen, Y., Park, H.‐J., Park, J., Song, H.‐C., Ryter, S. W., Surh, Y.‐J., Kim, U.‐H., Joe, Y., Chung, H. T. Carbon monoxide ameliorates acetaminophen‐induced liver injury by increasing hepatic HO‐1 and Parkin expression. FASEB J. 33, 13905‐13919 (2019). www.fasebj.org

Obesity-induced skeletal muscle inflammation is a major contributor of skeletal muscle loss/atrophy and is implicated in metabolic complications such as insulin resistance. Fibroblast growth factor 21 (FGF21) is known to be an important metabolic regulator with anti-inflammatory properties. However, the effect of FGF21 on skeletal muscle atrophy is unclear. In this study, we investigated the effect of FGF21 deficiency on obesity-induced skeletal muscle inflammation and atrophy in mice. The expression of atrophic factors (MuRF1 and Atrogin-1) was upregulated at the mRNA and/or protein levels in the skeletal muscle of FGF21-deficient obese mice compared with wild type obese control mice. This was accompanied by an increase in levels of inflammatory cytokines (TNFα and MCP-1) and a reduction in AMPK phosphorylation. FGF21 treatment markedly suppressed TNFα-mediated inflammatory and atrophic responses in cultured myotubes, and the actions of FGF21 were blunted by the AMPK inhibitor compound C. These findings suggest that FGF21 deficiency aggravates obesity-induced inflammation and atrophic responses in the skeletal muscle of obese mice, and FGF21 may protect inflammation-mediated atrophy through the AMPK pathway.