Joy Jiang

• MD. PhD
• Professor (Associate) at University of California, Davis

Background &Aims: Src homology and collagen (Shc) proteins are major adapters to extra-cellular signals however the regulatory role of Shc isoforms in sterile inflammatory responses in alcoholic hepatitis (AH) has not been fully investigated. We hypothesized that in an isoform-specific manner Shc modulates pre-apoptotic signals, calreticulin (CRT)...

Shc expression rises in human nonalcoholic steatohepatitis (NASH) livers, and Shc-deficient mice are protected from NASH—thus Shc inhibition could be a novel therapeutic strategy for NASH. Idebenone was recently identified as the first small-molecule Shc inhibitor drug. We tested idebenone in the fibrotic methionine-choline deficient (MCD) diet and...

Type 2 diabetes is clinically associated with progressive necroinflammation and fibrosis in nonalcoholic steatohepatitis (NASH). Advanced glycation end-products (AGEs) accumulate during prolonged hyperglycemia, but the mechanistic pathways that lead to accelerated liver fibrosis have not been well defined. In this study, we show that the AGEs clear...

Background and aims: Older patients with obesity/type II diabetes mellitus frequently present with advanced NASH. Whether this is due to specific molecular pathways that accelerate fibrosis during aging is unknown. Activation of the Src homology 2 domain-containing collagen-related (Shc) proteins and redox stress have been recognized in aging; how...

Saturated fatty acids (SFAs) (the "bad" fat), especially palmitate (PA), in the human diet are blamed for potential health risks such as obesity and cancer because of SFA-induced lipotoxicity. However, epidemiological results demonstrate a latent benefit of SFAs, and it remains elusive whether a certain low level of SFAs is physiologically essentia...

T The cardiac glycoside digoxin was identified as a potent suppressor of PKM2-HIF-1a pathway activation in liver injury mouse models via intraperitoneal injection. We have assessed the therapeutic effects of digoxin by the clinically relevant oral route to reduce non-alcoholic steatohepatitis (NASH) in mice and analyzed the cellular basis for this...

Lipotoxicity-associated diseases such as obesity and cancer are linked to mitochondrial dysfunction due to over digestion of saturated fatty acids (SFAs), especially palmitate (PA) in diet. However, the physiological level of SFAs consumption required for maintaining normal mitochondrial homeostasis and liver functions remains to be elucidated. Her...

Backgrounds and Aims Hepatic infiltration of neutrophils is a hallmark of steatohepatitis; however, the role of neutrophils in the progression of steatohepatitis remains unknown. Methods A clinically relevant mouse model of steatohepatitis induced by high-fat diet (HFD)-plus-binge ethanol feeding was used. Liver fibrosis was examined. In vitro cel...

The increased production of reactive oxygen species (ROS) has been postulated to play a key role in the progression of nonalcoholic fatty liver disease (NAFLD). However, the source of ROS and mechanisms underlying the development of NAFLD have yet to be established. We observed a significant up-regulation of a minor isoform of NADPH oxidase, NOX1,...

Recruitment of inflammatory cells is a major feature of alcoholic liver injury however; the signals and cellular sources regulating this are not well defined. C-C chemokine receptor type 2 (CCR2) is expressed by active hepatic stellate cells (HSC) and is a key monocyte recruitment signal. Activated HSC are also important sources of hydrogen peroxid...

Macrophage activation is an important feature of primary biliary cholangitis (PBC) pathogenesis and other cholestatic liver diseases. Galectin-3 (Gal3), a pleiotropic lectin, is produced by monocytic cells and macrophages. However, its role in PBC has not been addressed. We hypothesized that Gal3 is a key to induce NOD-like receptor family, pyrin d...

NASH is leading cause of liver injury, and patients with typeII DM are prone for aggressive disease. ROS play a key role in progression, and NOX4 is an important source of H2O2; but the mechanisms linking AGEs exposure to NOX4/RAGE signaling have been undefined. We hypothesized that circulating AGEs activate hepatocyte NOX4 via RAGE leading to prog...

Hepatocellular carcinoma (HCC) carries a poor prognosis with no effective treatment available other than liver transplantation for selected patients. Vascular invasion of HCC is one of the most important negative predictor of survival. As the regulation of invasion of HCC cells is not well understood, our aim was to study the mechanisms by which ga...

Reactive oxidative species (ROS) are believed to be involved in the progression of non-alcoholic steatohepatitis (NASH). However, little is known about the sources of ROS in hepatocytes or their role in disease progression. We studied the effects of NADPH oxidase 4 (NOX4) in liver tissues from patients with NASH and mice with steatohepatitis. Liver...

Oxidative stress is a common feature observed in a wide spectrum of chronic liver diseases including viral hepatitis, alcoholic, and nonalcoholic steatohepatitis. The nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) are emerging as major sources of reactive oxygen species (ROS). Several major isoforms are expressed in the liver,...

Oxidative stress is an important pathological feature of alcoholic liver disease. NADPH oxidase 4 (NOX4) is expressed in activated hepatic stellate cells (HSC), and is an important source of hydrogen peroxide, however; its role in early alcoholic liver injury is not well understood. We hypothesize that NOX4 in HSC is induced in alcoholic liver inju...

Galectin-3 a lectin family member is a known mediator of stellate cell activation and liver fibrosis, and active Kupffer cells (KC) are described as a major source of galectin 3 in the liver. Macrophages play a significant role in the pathogenesis of primary biliary cirrhosis (PBC) however, the early inflammatory events are not well described. We h...

Non-alcoholic steatohepatitis (NASH) is one of the most common chronic liver diseases worldwide (1). Despite the large number of studies published in the field, the molecular signals triggering the progression of NASH from simple steatosis to necroinflammation are still poorly understood. One of the most important and early features of progressive...

Unlabelled: Advanced glycation endproducts (AGEs) accumulate in patients with diabetes, yet the link between AGEs and inflammatory and fibrogenic activity in nonalcoholic steatohepatitis (NASH) has not been explored. Tumor necrosis factor alpha (TNF-α)-converting enzyme (TACE) is at the center of inflammatory processes. Because the main natural re...

Liver fibrosis is a wound healing process, the end result of chronic liver injury elicited by different noxious stimuli. Activated hepatic stellate cells or myofibroblasts and portal myofibroblasts are considered as the main producers of the extracellular matrix in the liver. Upon liver injury the quiescent stellate cells transdifferentiate into my...

Unlabelled: Hepatic methionine metabolism may play an essential role in regulating methylation status and liver injury in Wilson's disease (WD) through the inhibition of S-adenosylhomocysteine hydrolase (SAHH) by copper (Cu) and the consequent accumulation of S-adenosylhomocysteine (SAH). We studied the transcript levels of selected genes related...

Gal3 (galectin-3) has been known to be involved in the regulation of kidney, lung and liver fibrosis. We have reported a novel mechanism by which Gal3 contributes to fibrogenesis. Extracellular Gal3 is required for tethering of apoptotic bodies by HSC via cross-linking with integrin αvβ3, and consequently promoting HSC activation. On the other hand...

The self-renewal capacity ascribed to embryonic stem cells (ESC) is reminiscent of cancer cell proliferation, raising speculation that a common network of genes may regulate these traits. A search for general regulators of these traits yielded a set of microRNAs for which expression is highly enriched in human ESCs and liver cancer cells (HCC) but...

Reactive oxygen species (ROS) play a key role in chronic liver injury and fibrosis. Homologs of NADPH oxidases (NOXs) are major sources of ROS, but the exact role of the individual homologs in liver disease is unknown. Our goal was to determine the role of NOX4 in liver fibrosis induced by bile duct ligation (BDL) with the aid of the pharmacologica...

Hepatic stellate cells (HSC), the key fibrogenic cells of the liver, transdifferentiate into myofibroblasts upon phagocytosis of apoptotic hepatocytes. Galectin-3, a β-galactoside-binding lectin, is a regulator of the phagocytic process. In this study, our aim was to study the mechanism by which extracellular galectin-3 modulates HSC phagocytosis a...

Genomic location and conservation of miR-122 and Pkm2. (A) The location of miR-122 on chromosome 18 q arm is marked with a red bar. miR-122 is conserved in a large fraction of vertebrates. (B) The location of the Pkm2 3′UTR target sequence on chromosome 15 q arm is marked with a red bar. The target sequence predicted by MiRanda is located on 15:70,...

Genomic location and conservation of miR-122 and Pkm2. (A) The location of Pkm2 is indicated by a blue bar, and the predicted hybridization site by miR-122 is indicated by the purple bar. The target sequence is predicted by Target Scan computational tool. The large boxed region shows that the target sequence of miR-122 in the 3′UTR of Pkm2 is conse...

Reduction of endogenous Pkm2 expression by miR-122 modulates cellular proliferation. (A) HepG2 and Hep3B cells were transfected with siPkm2, precursor miR-122 molecules, or mock miRNA molecules. 24 hours (S1A) and 36 hours (S1B) post-transfection, five randomly chosen areas from 5 different wells in 24-well culture plates were stained with Hoecht a...

Predicted transcription start site of vertebrate RNAPII using Promoter2.0 and BDGP. (A) Genomic region between chr18:54,263,500–54,269,000 was evaluated for possible transcription start sequences using Promoter2.0 and Berkeley Drosophila Genome Project (BDGP). DNA sequence between chr18:54,263,800–54,265,000 yielded a highly likely promoter sequenc...

Overexpression of miR-122 is inversely correlated with IGF1R in HepG2 and Hep3B. Western blot assay of IGF1R in HepG2 and Hep3B overexpressing miR-122. (TIF)

The self-renewal capacity ascribed to hESCs is paralleled in cancer cell proliferation, suggesting that a common network of genes may facilitate the promotion of these traits. However, the molecular mechanisms that are involved in regulating the silencing of these genes as stem cells differentiate into quiescent cellular lineages remain poorly unde...

Hepatocyte apoptosis and activation of hepatic stellate cells (HSC) are critical events in fibrogenesis. We previously demonstrated that phagocytosis of apoptotic hepatocytes by HSC is profibrogenic. Based on this, as well as the observation that reduced nicotinamide adenine dinucleotide phosphate oxidase (NADPH) oxidase induction is central to fib...

The adipocyte hormone, leptin has been demonstrated to have profibrogenic actions in vitro and in animal models. However, no correlation was found between plasma leptin levels and fibrosis stage in humans. Thus, our aim was to study whether soluble leptin receptor (SLR) or free leptin index (FLI; calculated as the ratio of leptin to SLR), may corre...

Activation of hepatic stellate cells (HSC) results in their proliferation and in the secretion of extracellular matrix (ECM) proteins, which leads to hepatic fibrosis. microRNAs (miRNAs) have been shown to regulate various cell functions, such as proliferation, differentiation, and apoptosis. Hence, we have analyzed the miRNAs that were differentia...

We have previously shown that phagocytosis of apoptotic bodies (AB) by hepatic stellate cells (HSC) is profibrogenic. As HSC survival is central to the progression of liver fibrosis, our goal was to investigate if phagocytosis induces HSC survival. Apoptosis of phagocytosing HSC was studied in the presence of known apoptotic agents. The JAK/STAT- a...

Unlabelled: Leptin, a profibrogenic cytokine, plays an important role in the development of non-alcoholic steatohepatitis. Leptin also regulates immune responses, including macrophage phagocytic activity. Stellate cells are key elements in liver fibrogenesis, and previously we have demonstrated that phagocytosis of apoptotic bodies by stellate cel...

Nonalcoholic fatty liver disease (NAFLD) is a major form of chronic liver disease in adults and children. It is one of the consequences of the current obesity epidemic, and can progress to nonalcoholic steatohepatitis (NASH), characterized by steatosis, inflammation, and progressive fibrosis, ultimately leading to cirrhosis and end-stage liver dise...

Hepatic stellate cell activation is a main feature of liver fibrogenesis. We have previously shown that phagocytosis of apoptotic bodies by stellate cells induces procollagen alpha1 (I) and transforming growth factor beta (TGF-beta) expression in vitro. Here we have further investigated the downstream effects of phagocytosis by studying NADPH oxida...

At the vertebrate neuromuscular junction (nmj), ATP is known to be coreleased with acetylcholine from the synaptic vesicles. We have previously shown that the P2Y1 receptor is localized at the nmj. Here, we extend the findings to show that another nucleotide receptor, P2Y2, is also localized there and with P2Y1 jointly mediates trophic responses to...

The presence of a collagenous protein (ColQ) characterizes the collagen-tailed forms of acetylcholinesterase and butyrylcholinesterase at vertebrate neuromuscular junctions which is tethered in the synaptic basal lamina. ColQ subunits, differing mostly by their signal sequences, are encoded by transcripts ColQ-1 and ColQ-1a, which are differentiall...

Presynaptic motor neuron synthesizes and secretes acetylcholinesterase (AChE) at vertebrate neuromuscular junctions. In order to determine the retrograde role of muscle in regulating the expression of AChE in motor neuron, a chimeric co-culture of NG108-15 cell, a cholinergic cell line that resembles motor neuron, with chick myotube was established...

In vertebrate neuromuscular junctions (nmjs), adenosine 5'-triphosphate (ATP) is stored at the motor nerve terminals and is co-released with acetylcholine during neural stimulation. Several lines of evidence suggest that the synaptic ATP can act as a synapse-organizing factor at the nmjs, mediated by metabotropic P2Y(1) receptors. P2Y(1) receptor m...

The expression of acetylcholinesterase (AChE) is markedly increased during myogenic differentiation of C2C12 myoblasts to myotubes; the expression is mediated by intrinsic factor(s) during muscle differentiation. In order to analyze the molecular mechanisms regulating AChE expression during myogenic differentiation, a approximately 2.2-kb human ACh...