Although numerous functions of extracellular signalregulated kinase 1/2 (ERK1/2) are identified, a direct effect of ERK1/2 on liver steatosis has not been reported. Here, we show that ERK1/2 activity is compromised in livers of leptin receptor-deficient (db/db) mice. Adenovirusmediated activation of mitogen-activated protein kinase kinase 1 (MEK1), the upstream regulator of ERK1/2, significantly ameliorated liver steatosis in db/db mice, increased expression of genes related to fatty acid b-oxidation and triglyceride (TG) export and increased serum b-hydroxybutyrate (3-HB) levels. Opposite effects were observed in adenovirus-mediated ERK1/2 knockdown C57/B6J wild-type mice. Furthermore, autophagy and autophagy-related protein 7 (ATG7) expression were decreased or increased by ERK1/2 knockdown or activation, respectively, in primary hepatocytes and liver. Blockade of autophagy by the autophagy inhibitor chloroquine or adenovirus-mediated ATG7 knockdown reversed the ameliorated liver steatosis in recombinant adenoviruses construct expressing rat constitutively active MEK1 Ad-CA MEK1 db/db mice, decreased expression of genes related to fatty acid b-oxidation and TG export, and decreased serum 3-HB levels. Finally, ERK1/2 regulated ATG7 expression in a p38-dependent pathway. Taken together, these results identify a novel beneficial role for ERK1/2 in liver steatosis via promoting ATG7-dependent autophagy, which provides new insights into the mechanisms underlying liver steatosis and important hints for targeting ERK1/2 in treating liver steatosis.Nonalcoholic fatty liver disease involves a serious pathological change in liver (1). The initial stage of nonalcoholic fatty liver disease is liver steatosis, characterized by the excess deposition of triglyceride (TG) and/or cholesterol (TC) in liver (2). If uncontrolled, liver steatosis will progress to life-threatening diseases, such as liver cirrhosis and dysfunction (3). Abnormal hepatic lipid accumulation results from increased uptake of fatty acid/augmented de novo lipogenesis and/or decreased b-oxidation/impaired TG export (4).Autophagy, a cellular process that degrades intracellular organelles and proteins (5), has recently been demonstrated to regulate lipid metabolism (6,7). Lipid droplets are sequestered by autophagosome with the coordination of autophagy-related genes (ATGs). Autophagosome is then fused with lysosome (8) for the degradation of lipid droplets into free fatty acids (FFAs). FFAs are then degraded by mitochondrial b-oxidation to produce ATP or are reesterified into TG for storage (9). Impaired autophagy decreases hepatic fatty acid b-oxidation (FAO) and TG export and results in liver steatosis in mice (7,10), and fatty liver is ameliorated when hepatic autophagy is stimulated by certain compounds (11,12) or some signaling pathways (13) in various animal models.The mitogen-activated protein kinase-extracellular signalregulated kinase (MEK-ERK) signaling pathway is involved in a wide variety of cellular processes (14-16). Several lines of evidence, ...

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Although many biological functions of MAPK1/ERK2-MAPK3/ERK1 (mitogen-activated protein kinase 1/3) have been reported, a direct effect of MAPK1/3 on hepatic lipid metabolism remains largely unknown. We recently showed that activation of MAPK1/3 ameliorates liver steatosis in LEPR (leptin receptor)-deficient (db/db) mice, a classic animal model for liver steatosis. Consistent with these results, knockdown of MAPK1/3 promotes liver steatosis in C57/B6J wild-type (WT) mice. Autophagic flux and ATG7 (autophagy related 7) levels are increased by MAPK1/3 activation or decreased by MAPK1/3 knockdown in livers and primary hepatocytes. Blockade of autophagic flux by chloroquine (CQ) or ATG7 knockdown reverses the ameliorated liver steatosis in MAPK1/3-activated db/db mice. Together, these findings identify a beneficial role for MAPK1/3 in liver steatosis that is mediated by ATG7-dependent autophagy, which provides novel insights into the mechanisms underlying liver steatosis and create a rationale for targeting MAPK1/3 in the treatment of liver steatosis.

SUMMARY Elucidating cell lineages provides crucial understanding of development. Recently developed sequencing-based techniques enhance the scale of lineage tracing but eliminate the spatial information offered by conventional approaches. Multi-spectral labeling techniques, such as Brainbow, have the potential to identify lineage-related cells in situ. Here, we report nuclear Bitbow (nBitbow), a “digital” version of Brainbow that greatly expands the color diversity for scoring cells, and a suite of statistical methods for quantifying the lineage relationship of any two cells. Applying these tools to the Drosophila peripheral nervous system (PNS), we determined lineage relationship between all neuronal pairs. This study demonstrates nBitbow as an efficient tool for in situ lineage mapping, and the complete lineage relationship among larval PNS neurons opens new possibilities for studying how neurons gain specific features and circuit connectivity.

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Mesencephalic astrocyte‐derived neurotrophic factor (MANF) is a unique member of the neurotrophic factor family residing in the endoplasmic reticulum, where it functions as a stress response protein maintaining endoplasmic reticulum homeostasis, in addition to being secreted extracellularly as a neurotrophic factor to bind with receptors to initiate intracellular signal transduction pathways. Interestingly, MANF has shown an important protective role in the inflammatory response of many diseases. In neural stem cells, pancreatic β cells, and retinal cells, MANF can inhibit the inflammatory response, modulate the immune response, and promote tissue repair. However, the role of MANF in the periodontal inflammatory response remains unclear. In the present study, we used lipopolysaccharide (LPS) from Porphyromonas gingivalis (Pg) to establish a Pg‐LPS‐stimulated periodontal inflammatory model in human gingival fibroblasts cells (HGF‐1) to investigate the role of MANF in vitro. We found that MANF could inhibit pro‐inflammatory cytokine secretion, alleviate the endoplasmic reticulum stress response, promote cell survival, and inhibit cell apoptosis. Therefore, MANF might be a novel promising target for the treatment of periodontitis.