The focus then turns to neuropsychological investigations of the cognitive basis of symptoms

which, although unusual in the broader context of a dementia clinic, are particularly characteristic of the PCA syndrome, before exploring implications for clinical management and patient and carer support. “
“We selleck chemicals llc studied the effects of optokinetic stimulation (OKS; leftward, rightward, control) on the visuo-perceptual and number space, in the same sample, during line bisection and mental number interval bisection tasks. To this end, we tested six patients with right-hemisphere damage and neglect, six patients with right-hemisphere damage but without neglect, and six neurologically healthy participants. In patients with neglect, we found a strong effect KPT-330 cost of leftward OKS on line bisection, but not on mental number interval bisection. We suggest

that OKS influences the number space only under specific conditions. “
“Theory of Mind (ToM) allows one’s own and others’ cognitive and emotional mental states to be inferred. Although many patients with Alzheimer’s disease (AD) display impaired social functioning as their disease progresses, very few studies have investigated ToM in AD. Those that have done so suggest that patients’ ToM deficits are the consequence of other cognitive impairments. The aim of this study was thus to investigate changes in both the cognitive and the affective dimensions of ToM in AD, using tasks designed to circumvent the patients’ comprehension this website difficulties. Sixteen mild to moderate AD patients and 15 healthy controls matched on age, sex and education level underwent cognitive (preference judgment and first- and second-order false belief) and affective (Reading the Mind in the Eyes) ToM assessments. Comprehension of false belief stories was verified and an additional neuropsychological

examination was undergone. We observed impaired performances by AD patients on all the ToM tasks. While working memory and executive functioning impairments contributed to the deterioration in the more complex aspects of cognitive ToM abilities as highlighted by a correlation analysis, we failed to observe any comprehension difficulties in patients who performed poorly on simple cognitive ToM tasks, which suggests that AD truly affects cognitive ToM. “
“Information processing difficulties are common in patients with chronic fatigue syndrome (CFS). It has been shown that the time it takes to process a complex cognitive task, rather than error rate, may be the critical variable underlying CFS patients’ cognitive complaints. The Attention Network Task (ANT) developed by Fan and colleagues may be of clinical utility to assess cognitive function in CFS, because it allows for simultaneous assessment of mental response speed, also called information processing speed, and error rate under three conditions challenging the attention system.

However, the diagnosis of fatty change, established cirrhosis and hepatocellular carcinoma may be suggested by ultrasound, computed tomography scan, or magnetic resonance imaging (MRI) and confirmed by other laboratory investigations.143, 144 The major value of imaging studies is to exclude other causes of abnormal liver tests in a patient who abuses alcohol, such as obstructive biliary pathology, or infiltrative and neoplastic diseases

of the liver.145 MRI has been used as an adjunct to diagnose cirrhosis, and to distinguish end-stage liver disease related to viral hepatitis infection from ALD. Specific features that may be suggestive of alcoholic cirrhosis include a higher volume index of the caudate lobe, RAD001 clinical trial more frequent visualization of the

right posterior hepatic notch, and smaller size of regenerative nodules of the liver in patients with cirrhosis on the basis of ALD versus chronic viral hepatitis.146 Although changes were identified on ultrasound and MRI, it is unclear whether these results are generalizable.146, MG-132 cost 147 Although not essential in the management of ALD, a liver biopsy is useful in establishing the diagnosis.144 As many as 20% of patients with a history of alcohol abuse have a secondary or coexisting etiology for liver disease.148 In the absence of decompensated disease, clinical and biochemical indicators are poor markers of the severity of liver disease, and a biopsy is useful in establishing the stage and severity of liver disease.144, 149 The histological features of alcohol-induced hepatic injury vary, depending on the extent and stage of injury. These may include steatosis (fatty change), lobular inflammation,

periportal fibrosis, Mallory bodies, nuclear vacuolation, bile ductal proliferation, and fibrosis or cirrhosis.24 These may coexist in the same biopsy, however, and are not individually pathognomonic of ALD. The clinical diagnosis of AH is made based on a typical presentation, with severe liver dysfunction in the context of excessive alcohol consumption, and the exclusion of other causes of acute and chronic liver disease. In the subset of patients selleckchem with AH, a liver biopsy may demonstrate specific histologic features, including confluent parenchymal necrosis, steatosis, deposition of intrasinusoidal and pericentral collagen, ballooning degeneration, and lobular inflammation affecting the perivenular regions in the earliest stages.34 The liver may be infiltrated with polymorphonuclear cells, typically clustered around cytoplasmic structures known as Mallory bodies,150 which represent aggregated cytokeratin intermediate filaments and other proteins. In addition to confirming the diagnosis and staging the extent of disease, specific features on liver biopsy also convey prognostic importance. The severity of inflammation (i.e.

However, the diagnosis of fatty change, established cirrhosis and hepatocellular carcinoma may be suggested by ultrasound, computed tomography scan, or magnetic resonance imaging (MRI) and confirmed by other laboratory investigations.143, 144 The major value of imaging studies is to exclude other causes of abnormal liver tests in a patient who abuses alcohol, such as obstructive biliary pathology, or infiltrative and neoplastic diseases

of the liver.145 MRI has been used as an adjunct to diagnose cirrhosis, and to distinguish end-stage liver disease related to viral hepatitis infection from ALD. Specific features that may be suggestive of alcoholic cirrhosis include a higher volume index of the caudate lobe, Selleckchem PR-171 more frequent visualization of the

right posterior hepatic notch, and smaller size of regenerative nodules of the liver in patients with cirrhosis on the basis of ALD versus chronic viral hepatitis.146 Although changes were identified on ultrasound and MRI, it is unclear whether these results are generalizable.146, Selleckchem beta-catenin inhibitor 147 Although not essential in the management of ALD, a liver biopsy is useful in establishing the diagnosis.144 As many as 20% of patients with a history of alcohol abuse have a secondary or coexisting etiology for liver disease.148 In the absence of decompensated disease, clinical and biochemical indicators are poor markers of the severity of liver disease, and a biopsy is useful in establishing the stage and severity of liver disease.144, 149 The histological features of alcohol-induced hepatic injury vary, depending on the extent and stage of injury. These may include steatosis (fatty change), lobular inflammation,

periportal fibrosis, Mallory bodies, nuclear vacuolation, bile ductal proliferation, and fibrosis or cirrhosis.24 These may coexist in the same biopsy, however, and are not individually pathognomonic of ALD. The clinical diagnosis of AH is made based on a typical presentation, with severe liver dysfunction in the context of excessive alcohol consumption, and the exclusion of other causes of acute and chronic liver disease. In the subset of patients see more with AH, a liver biopsy may demonstrate specific histologic features, including confluent parenchymal necrosis, steatosis, deposition of intrasinusoidal and pericentral collagen, ballooning degeneration, and lobular inflammation affecting the perivenular regions in the earliest stages.34 The liver may be infiltrated with polymorphonuclear cells, typically clustered around cytoplasmic structures known as Mallory bodies,150 which represent aggregated cytokeratin intermediate filaments and other proteins. In addition to confirming the diagnosis and staging the extent of disease, specific features on liver biopsy also convey prognostic importance. The severity of inflammation (i.e.

4A. Light microscopic evaluation showed roughly similar morphologic appearance among the three phenotypes, although hepatocytes isolated this website from ApoE−/− mice showed more discontinuities of the plasma membrane and marked reduction in brightness contrast between the nucleus and cytoplasm (Fig. 4A). These early changes of injury were consistent with the observation that hepatocytes isolated from ApoE−/− mice exhibited an increased caspase 3/7 activity, indicative of enhanced

apoptosis (Fig. 4B). Enhanced apoptosis was not observed in cultures of hepatocytes isolated from ApoE−/−/5-LO−/− mice, in which caspase 3/7 activity was similar to that of WT animals (Fig. 4B). These phenomena were more evident in hepatocytes sensitized to TNF-α–induced cell death by treatment with the RNA synthesis inhibitor, actinomycin D, which blocks the up-regulation of the expression of NF-κB–dependent protective survival genes (Fig. 4B).24 We also tested the direct effects of 5-LO products on hepatocyte apoptosis. The addition of nanomolar concentrations of the 5-LO products LTB4 (Fig. 4C), LTD4(Fig. 4D), and 5-HETE (Fig. 4E) to hepatocytes did not compromise their survival. However, these

5-LO products sensitized hepatocytes to TNF-α–induced apoptosis and synergistically Cobimetinib datasheet potentiated the apoptotic effects of actinomycin D (Fig. 4C-E). The modulation of hepatocyte survival by 5-LO products appeared to be mediated by specific surface receptors, because U-75302, a LTB4 receptor antagonist, and MK-571, a LTD4 receptor antagonist, prevented caspase 3/7 induction (Fig. 4C,D). Together, these findings indicate that 5-LO products sensitize hepatocytes to apoptosis. Because the transcription factor NF-κB plays a pivotal

role in the crossroads of life and death in hepatocytes,24, 25 we next assessed the effects of 5-LO products on NF-κB activity in hepatocytes in culture. Confirming previous findings in the vascular bed,26, 27 5-LO products induced NF-κB activity in hepatocytes to a similar extent as that of TNF-α (Fig. 5A). In contrast, in the presence learn more of TNF-α and actinomycin D, which is an apoptotic condition in which NF-κB is critical for hepatocyte survival, LTB4, LTD4, and 5-HETE exerted a significant inhibition of this transcription factor (Fig. 5B). To confirm in vivo the in vitro findings, cleaved caspase-3 activity, an established marker of apoptosis, and NF-κB activity were assessed in samples of liver tissue from WT, ApoE−/−, and ApoE−/−/5-LO−/− mice. As compared with WT mice, caspase-3 immunostaining and NF-κB activity were significantly increased in liver samples from ApoE−/− mice, effects that were abrogated by the genetic disruption of Alox5 in ApoE−/−/5-LO−/− mice (Fig. 6). To evaluate the extent to which the absence of 5-LO alters the response of the liver to sustained injury, the three groups of mice of the study were fed an HFD, making them more susceptible to liver injury.

4A. Light microscopic evaluation showed roughly similar morphologic appearance among the three phenotypes, although hepatocytes isolated MG-132 mouse from ApoE−/− mice showed more discontinuities of the plasma membrane and marked reduction in brightness contrast between the nucleus and cytoplasm (Fig. 4A). These early changes of injury were consistent with the observation that hepatocytes isolated from ApoE−/− mice exhibited an increased caspase 3/7 activity, indicative of enhanced

apoptosis (Fig. 4B). Enhanced apoptosis was not observed in cultures of hepatocytes isolated from ApoE−/−/5-LO−/− mice, in which caspase 3/7 activity was similar to that of WT animals (Fig. 4B). These phenomena were more evident in hepatocytes sensitized to TNF-α–induced cell death by treatment with the RNA synthesis inhibitor, actinomycin D, which blocks the up-regulation of the expression of NF-κB–dependent protective survival genes (Fig. 4B).24 We also tested the direct effects of 5-LO products on hepatocyte apoptosis. The addition of nanomolar concentrations of the 5-LO products LTB4 (Fig. 4C), LTD4(Fig. 4D), and 5-HETE (Fig. 4E) to hepatocytes did not compromise their survival. However, these

5-LO products sensitized hepatocytes to TNF-α–induced apoptosis and synergistically PD0332991 price potentiated the apoptotic effects of actinomycin D (Fig. 4C-E). The modulation of hepatocyte survival by 5-LO products appeared to be mediated by specific surface receptors, because U-75302, a LTB4 receptor antagonist, and MK-571, a LTD4 receptor antagonist, prevented caspase 3/7 induction (Fig. 4C,D). Together, these findings indicate that 5-LO products sensitize hepatocytes to apoptosis. Because the transcription factor NF-κB plays a pivotal

role in the crossroads of life and death in hepatocytes,24, 25 we next assessed the effects of 5-LO products on NF-κB activity in hepatocytes in culture. Confirming previous findings in the vascular bed,26, 27 5-LO products induced NF-κB activity in hepatocytes to a similar extent as that of TNF-α (Fig. 5A). In contrast, in the presence selleck of TNF-α and actinomycin D, which is an apoptotic condition in which NF-κB is critical for hepatocyte survival, LTB4, LTD4, and 5-HETE exerted a significant inhibition of this transcription factor (Fig. 5B). To confirm in vivo the in vitro findings, cleaved caspase-3 activity, an established marker of apoptosis, and NF-κB activity were assessed in samples of liver tissue from WT, ApoE−/−, and ApoE−/−/5-LO−/− mice. As compared with WT mice, caspase-3 immunostaining and NF-κB activity were significantly increased in liver samples from ApoE−/− mice, effects that were abrogated by the genetic disruption of Alox5 in ApoE−/−/5-LO−/− mice (Fig. 6). To evaluate the extent to which the absence of 5-LO alters the response of the liver to sustained injury, the three groups of mice of the study were fed an HFD, making them more susceptible to liver injury.

Long-term risks of bone fractures, peripheral weight gain, and the potential to develop congestive heart failure remain with both TZDs. Therefore, the risk-benefit ratio should be considered in each patient prior to initiating adjuvant therapy with a TZD. “
“See Article on Page 1631 Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the United States and consists of a spectrum of diseases ranging from relatively benign steatosis to more aggressive steatohepatitis (NASH), which can lead to cirrhosis and liver failure. Obesity, type 2 diabetes, and metabolic

syndrome are closely associated with NAFLD and NASH. Adipose tissue insulin resistance is believed to be one of the fundamental mechanisms leading to an increased hepatic selleck chemical influx of nonesterified fatty acids (NEFA).1, 2 In addition, increased de novo lipogenesis and dietary intake also contribute to the accumulation of hepatic lipids.

An increased hepatic fatty acid load is thought to be lipotoxic, either through toxic lipid-intermediaries CHIR-99021 or by causing oxidative stress.3 Fatty acid oxidation by mitochondria, microsomes, and peroxisomes leads to oxidative stress and increased lipid peroxidation. Peripheral insulin resistance and oxidative stress have been the main therapeutic targets and previously clinical trials have almost exclusively investigated insulin sensitizers and antioxidants to treat NASH. HSC, selleck hepatic stellate cells; NASH, nonalcoholic steatohepatitis; NEFA, nonesterified fatty acids; TZD, thiazolidinediones. Lifestyle modification leading to sustained weight loss can be an effective treatment for NASH but is difficult to achieve and, importantly, more difficult to sustain. Thus, there has been significant interest in developing pharmacological agents to treat NASH, and insulin

sensitizers such as metformin and thiazolidinediones (rosiglitazone and pioglitazone) and antioxidants such as vitamin E have been investigated to treat NASH. A recently published meta-analysis concluded that metformin is not effective in improving liver histology in adults with NASH3 and the recently published TONIC trial showed that metformin administered at a daily dose of 1 g is of no benefit to children with NAFLD.4 However, pioglitazone and rosiglitazone have shown effectiveness in improving liver histology, primarily in nondiabetic adults with NASH.3 The meta-analysis by Musso et al.3 summarized that thiazolidinediones (TZDs) improve steatosis (odds ratio [OR] 4.05, 95% confidence interval [CI] 2.58-6.35) and inflammation (OR 3.53, 95% CI 2.21-5.64) but not fibrosis (OR 1.40, 95% CI 0.87-2.24). Two randomized controlled trials conducted by the NASH Clinical Research Network have shown that vitamin E administered at a daily dose of 800 IU improves liver histology both in adults and in children.

Long-term risks of bone fractures, peripheral weight gain, and the potential to develop congestive heart failure remain with both TZDs. Therefore, the risk-benefit ratio should be considered in each patient prior to initiating adjuvant therapy with a TZD. “
“See Article on Page 1631 Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the United States and consists of a spectrum of diseases ranging from relatively benign steatosis to more aggressive steatohepatitis (NASH), which can lead to cirrhosis and liver failure. Obesity, type 2 diabetes, and metabolic

syndrome are closely associated with NAFLD and NASH. Adipose tissue insulin resistance is believed to be one of the fundamental mechanisms leading to an increased hepatic www.selleckchem.com/products/napabucasin.html influx of nonesterified fatty acids (NEFA).1, 2 In addition, increased de novo lipogenesis and dietary intake also contribute to the accumulation of hepatic lipids.

An increased hepatic fatty acid load is thought to be lipotoxic, either through toxic lipid-intermediaries Carfilzomib price or by causing oxidative stress.3 Fatty acid oxidation by mitochondria, microsomes, and peroxisomes leads to oxidative stress and increased lipid peroxidation. Peripheral insulin resistance and oxidative stress have been the main therapeutic targets and previously clinical trials have almost exclusively investigated insulin sensitizers and antioxidants to treat NASH. HSC, selleckchem hepatic stellate cells; NASH, nonalcoholic steatohepatitis; NEFA, nonesterified fatty acids; TZD, thiazolidinediones. Lifestyle modification leading to sustained weight loss can be an effective treatment for NASH but is difficult to achieve and, importantly, more difficult to sustain. Thus, there has been significant interest in developing pharmacological agents to treat NASH, and insulin

sensitizers such as metformin and thiazolidinediones (rosiglitazone and pioglitazone) and antioxidants such as vitamin E have been investigated to treat NASH. A recently published meta-analysis concluded that metformin is not effective in improving liver histology in adults with NASH3 and the recently published TONIC trial showed that metformin administered at a daily dose of 1 g is of no benefit to children with NAFLD.4 However, pioglitazone and rosiglitazone have shown effectiveness in improving liver histology, primarily in nondiabetic adults with NASH.3 The meta-analysis by Musso et al.3 summarized that thiazolidinediones (TZDs) improve steatosis (odds ratio [OR] 4.05, 95% confidence interval [CI] 2.58-6.35) and inflammation (OR 3.53, 95% CI 2.21-5.64) but not fibrosis (OR 1.40, 95% CI 0.87-2.24). Two randomized controlled trials conducted by the NASH Clinical Research Network have shown that vitamin E administered at a daily dose of 800 IU improves liver histology both in adults and in children.

Long-term risks of bone fractures, peripheral weight gain, and the potential to develop congestive heart failure remain with both TZDs. Therefore, the risk-benefit ratio should be considered in each patient prior to initiating adjuvant therapy with a TZD. “
“See Article on Page 1631 Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the United States and consists of a spectrum of diseases ranging from relatively benign steatosis to more aggressive steatohepatitis (NASH), which can lead to cirrhosis and liver failure. Obesity, type 2 diabetes, and metabolic

syndrome are closely associated with NAFLD and NASH. Adipose tissue insulin resistance is believed to be one of the fundamental mechanisms leading to an increased hepatic Selleck Ponatinib influx of nonesterified fatty acids (NEFA).1, 2 In addition, increased de novo lipogenesis and dietary intake also contribute to the accumulation of hepatic lipids.

An increased hepatic fatty acid load is thought to be lipotoxic, either through toxic lipid-intermediaries Selleckchem Stem Cell Compound Library or by causing oxidative stress.3 Fatty acid oxidation by mitochondria, microsomes, and peroxisomes leads to oxidative stress and increased lipid peroxidation. Peripheral insulin resistance and oxidative stress have been the main therapeutic targets and previously clinical trials have almost exclusively investigated insulin sensitizers and antioxidants to treat NASH. HSC, selleck screening library hepatic stellate cells; NASH, nonalcoholic steatohepatitis; NEFA, nonesterified fatty acids; TZD, thiazolidinediones. Lifestyle modification leading to sustained weight loss can be an effective treatment for NASH but is difficult to achieve and, importantly, more difficult to sustain. Thus, there has been significant interest in developing pharmacological agents to treat NASH, and insulin

sensitizers such as metformin and thiazolidinediones (rosiglitazone and pioglitazone) and antioxidants such as vitamin E have been investigated to treat NASH. A recently published meta-analysis concluded that metformin is not effective in improving liver histology in adults with NASH3 and the recently published TONIC trial showed that metformin administered at a daily dose of 1 g is of no benefit to children with NAFLD.4 However, pioglitazone and rosiglitazone have shown effectiveness in improving liver histology, primarily in nondiabetic adults with NASH.3 The meta-analysis by Musso et al.3 summarized that thiazolidinediones (TZDs) improve steatosis (odds ratio [OR] 4.05, 95% confidence interval [CI] 2.58-6.35) and inflammation (OR 3.53, 95% CI 2.21-5.64) but not fibrosis (OR 1.40, 95% CI 0.87-2.24). Two randomized controlled trials conducted by the NASH Clinical Research Network have shown that vitamin E administered at a daily dose of 800 IU improves liver histology both in adults and in children.

SREBPs are known to be important transcription factors and play a central role in lipid homeostasis; however, there is yet no evidence that links SREBP to the lipogenic effect of RBP4. Our present results reveal that in HepG2 cells, stimulation with human recombinant RBP4 did not affect the protein expression of SREBP-1, but rather reduced the nuclear mature form of SREBP-1, thus leading to a potent induction of its target http://www.selleckchem.com/products/poziotinib-hm781-36b.html genes as well as lipid accumulation in vitro. However,

SREBP-2 predominantly regulates genes controlling cholesterol homeostasis, such as LDLR, HMG coenzyme A reductase, and squalene synthase[36, 37] was not affected in response to RBP4. These results are consistent with previous findings that hepatic overexpression of SREBP-1 induced lipogenesis.[21] SREBP-1a and SREBP-1c mainly regulates the transcription of key enzymes associated with the biosynthesis of fatty acids and the lipogenic process, although in the HepG2 cells, there check details are more SREBP-1a isoforms than SREBP-1c, but only the SREBP-1c promoter is transcriptionally activated in response to RBP4 treatment. This is demonstrated by our results that the transcription level of SREBP-1c is greatly induced by RBP4 treatment, while SREBP-1a is not significantly changed. Thus, the induced

protein levels of SREBP-1 under RBP4 treatment is mainly from induced SREBP-1c, not SREBP-1a. Therefore, SREBP-1c might be the primary isoform of RBP4 action. Deletion analysis of the SREBP-1c promoter further showed that activity of the WT SREBP-1c promoter, but not SRE or the LXRE deletion promoter, was induced by RBP4. This study indicates that RBP4 functions as a potential adipokine that controls SREBP-1c transcriptional activity through autoloop regulation by way of an SRE/LXRE motif-dependent mechanism. Further studies with the use of

SREBP-1c knockout mice are necessary to prove this feedforward mechanism. On the contrary, RBP4 exerted less effect on SREBP-2 transcriptional activity, click here as demonstrated by nuclear SREBP-2-induced autoregulation and the transcription of HMG-CoA and LDLR. These results strengthened the conclusion that the induction of lipogenesis by RBP4 is mainly dependent on SREBP-1c. We further found that PGC-1β is a critical effector downstream of RBP4, which mediates RBP4 effects on the induction of SREBP-1c and thus promotes hepatic lipogenesis. Originally, PGC-1β was identified as the closest homolog of PGC-1α and a cold-inducible coactivator that interacts with peroxisome proliferator-activated receptor gamma (PPARγ) in brown adipose tissue.[38] PGC-1β is most highly expressed in tissues with high oxidative metabolism, such as brown adipose tissue, cardiac muscle, and skeletal muscle.[38, 39] PGC-1β coactivates the SREBP and LXR families of transcription factors, as it induces a broad program of lipid metabolism, including de novo lipogenesis and lipoprotein secretion.

SREBPs are known to be important transcription factors and play a central role in lipid homeostasis; however, there is yet no evidence that links SREBP to the lipogenic effect of RBP4. Our present results reveal that in HepG2 cells, stimulation with human recombinant RBP4 did not affect the protein expression of SREBP-1, but rather reduced the nuclear mature form of SREBP-1, thus leading to a potent induction of its target PD98059 manufacturer genes as well as lipid accumulation in vitro. However,

SREBP-2 predominantly regulates genes controlling cholesterol homeostasis, such as LDLR, HMG coenzyme A reductase, and squalene synthase[36, 37] was not affected in response to RBP4. These results are consistent with previous findings that hepatic overexpression of SREBP-1 induced lipogenesis.[21] SREBP-1a and SREBP-1c mainly regulates the transcription of key enzymes associated with the biosynthesis of fatty acids and the lipogenic process, although in the HepG2 cells, there selleck compound are more SREBP-1a isoforms than SREBP-1c, but only the SREBP-1c promoter is transcriptionally activated in response to RBP4 treatment. This is demonstrated by our results that the transcription level of SREBP-1c is greatly induced by RBP4 treatment, while SREBP-1a is not significantly changed. Thus, the induced

protein levels of SREBP-1 under RBP4 treatment is mainly from induced SREBP-1c, not SREBP-1a. Therefore, SREBP-1c might be the primary isoform of RBP4 action. Deletion analysis of the SREBP-1c promoter further showed that activity of the WT SREBP-1c promoter, but not SRE or the LXRE deletion promoter, was induced by RBP4. This study indicates that RBP4 functions as a potential adipokine that controls SREBP-1c transcriptional activity through autoloop regulation by way of an SRE/LXRE motif-dependent mechanism. Further studies with the use of

SREBP-1c knockout mice are necessary to prove this feedforward mechanism. On the contrary, RBP4 exerted less effect on SREBP-2 transcriptional activity, click here as demonstrated by nuclear SREBP-2-induced autoregulation and the transcription of HMG-CoA and LDLR. These results strengthened the conclusion that the induction of lipogenesis by RBP4 is mainly dependent on SREBP-1c. We further found that PGC-1β is a critical effector downstream of RBP4, which mediates RBP4 effects on the induction of SREBP-1c and thus promotes hepatic lipogenesis. Originally, PGC-1β was identified as the closest homolog of PGC-1α and a cold-inducible coactivator that interacts with peroxisome proliferator-activated receptor gamma (PPARγ) in brown adipose tissue.[38] PGC-1β is most highly expressed in tissues with high oxidative metabolism, such as brown adipose tissue, cardiac muscle, and skeletal muscle.[38, 39] PGC-1β coactivates the SREBP and LXR families of transcription factors, as it induces a broad program of lipid metabolism, including de novo lipogenesis and lipoprotein secretion.