Hong-Ping Guan - Academia.edu (original) (raw)

Papers by Hong-Ping Guan

American journal of physiology. Endocrinology and metabolism, 2007

Peroxisome proliferator-activated receptor-gamma (PPARgamma) regulates adipocyte genes involved i... more Peroxisome proliferator-activated receptor-gamma (PPARgamma) regulates adipocyte genes involved in adipogenesis and lipid metabolism and is the molecular target for thiazolidinedione (TZD) antidiabetic agents. Adipose triglyceride lipase (ATGL) is a recently described triglyceride-specific lipase that is induced during adipogenesis and remains highly expressed in mature adipocytes. This study evaluates the ability of PPARgamma to directly regulate ATGL expression in adipocytes in vitro and in vivo. In fully differentiated 3T3-L1 adipocytes, ATGL mRNA and protein are increased by TZD and non-TZD PPARgamma agonists in a dose- and time-dependent manner. Rosiglitazone-mediated induction of ATGL mRNA is rapid and is not inhibited by the protein synthesis inhibitor cycloheximide, indicating that intervening protein synthesis is not required for this effect. Rosiglitazone-mediated induction of ATGL mRNA and protein is inhibited by the PPARgamma-specific antagonist GW-9662 and is also signi...

The Journal of clinical investigation, 2005

In addition to its role in energy storage, adipose tissue also accumulates cholesterol. Concentra... more In addition to its role in energy storage, adipose tissue also accumulates cholesterol. Concentrations of cholesterol and triglycerides are strongly correlated in the adipocyte, but little is known about mechanisms regulating cholesterol metabolism in fat cells. Here we report that antidiabetic thiazolidinediones (TZDs) and other ligands for the nuclear receptor PPARgamma dramatically upregulate oxidized LDL receptor 1 (OLR1) in adipocytes by facilitating the exchange of coactivators for corepressors on the OLR1 gene in cultured mouse adipocytes. TZDs markedly stimulate the uptake of oxidized LDL (oxLDL) into adipocytes, and this requires OLR1. Increased OLR1 expression, resulting either from TZD treatment or adenoviral gene delivery, significantly augments adipocyte cholesterol content and enhances fatty acid uptake. OLR1 expression in white adipose tissue is increased in obesity and is further induced by PPARgamma ligand treatment in vivo. Serum oxLDL levels are decreased in both ...

Acta neuropathologica, 2003

Mutations in the gene encoding alpha-synuclein (alpha-syn) have recently been linked to rare here... more Mutations in the gene encoding alpha-synuclein (alpha-syn) have recently been linked to rare hereditary forms of Parkinson's disease. A yeast two-hybrid screen with alpha-synuclein (alpha-syn) identified synphilin as an alpha-syn-interacting protein, potentially implicating synphilin in the pathogenesis of synucleinopathies. Co-transfection of synphilin and the central (NAC) region of alpha-syn in HEH293 cells resulted in synuclein inclusions. Furthermore, synphilin immunoreactivity has been observed in Lewy bodies (LBs) and glial cytoplasmic inclusions of synucleinopathies. To further characterize synphilin, we utilized two new anti-synphilin antibodies for biochemical and immunohistochemical studies in normal and disease brain tissues. In normal brain tissue, synphilin localized predominantly to large neurons, such as substantia nigra neurons, hippocampal pyramidal and cerebellar Purkinje cells. However, in a few pathological cases synphilin immunoreactivity was present in gli...

The Journal of Lipid Research, 2013

Hepatic glucose overproduction is a major characteristic of type 2 diabetes. Because glucagon is ... more Hepatic glucose overproduction is a major characteristic of type 2 diabetes. Because glucagon is a key regulator for glucose homeostasis, antagonizing the glucagon receptor (GCGR) is a possible therapeutic strategy for the treatment of diabetes mellitus. To study the effect of hepatic GCGR inhibition on the regulation of lipid metabolism, we generated siRNA-mediated GCGR knockdown (si-GCGR) in the db/db mouse. The hepatic knockdown of GCGR markedly reduced plasma glucose levels; however, total plasma cholesterol was increased. The detailed lipid analysis showed an increase in the LDL fraction, and no change in VLDL HDL fractions. Further studies showed that the increase in LDL was the result of over-expression of hepatic lipogenic genes and elevated de novo lipid synthesis. Inhibition of hepatic glucagon signaling via siRNA-mediated GCGR knockdown had an effect on both glucose and lipid metabolism in db/db mice.

Journal of Clinical Investigation, 2005

In addition to its role in energy storage, adipose tissue also accumulates cholesterol. Concentra... more In addition to its role in energy storage, adipose tissue also accumulates cholesterol. Concentrations of cholesterol and triglycerides are strongly correlated in the adipocyte, but little is known about mechanisms regulating cholesterol metabolism in fat cells. Here we report that antidiabetic thiazolidinediones (TZDs) and other ligands for the nuclear receptor PPARγ dramatically upregulate oxidized LDL receptor 1 (OLR1) in adipocytes by facilitating the exchange of coactivators for corepressors on the OLR1 gene in cultured mouse adipocytes. TZDs markedly stimulate the uptake of oxidized LDL (oxLDL) into adipocytes, and this requires OLR1. Increased OLR1 expression, resulting either from TZD treatment or adenoviral gene delivery, significantly augments adipocyte cholesterol content and enhances fatty acid uptake. OLR1 expression in white adipose tissue is increased in obesity and is further induced by PPARγ ligand treatment in vivo. Serum oxLDL levels are decreased in both lean and obese diabetic animals treated with TZDs. These data identify OLR1 as a novel PPARγ target gene in adipocytes. While the physiological role of adipose tissue in cholesterol and oxLDL metabolism remains to be established, the induction of OLR1 is a potential means by which PPARγ ligands regulate lipid metabolism and insulin sensitivity in adipocytes.

Journal of Biological Chemistry, 2009

The accumulation of triglycerides (TG) in the liver, designated hepatic steatosis, is characteris... more The accumulation of triglycerides (TG) in the liver, designated hepatic steatosis, is characteristically associated with obesity and insulin resistance, but it can also develop after fasting. Here, we show that fasting-induced hepatic steatosis is under genetic control in inbred mice. After a 24-h fast, C57BL/6J mice and SJL/J mice both lost more than 20% of body weight and approximately 60% of total body TG. In C57BL/6J mice, TG accumulated in liver, producing frank steatosis. In striking contrast, SJL/J mice failed to accumulate any hepatic TG even though they lost nearly as much adipose tissue mass as the C57BL/6J mice. Mice from five other inbred strains developed fasting-induced steatosis like the C57BL/6J mice. Measurements of the uptake of free fatty acids (FA) in vivo and in vitro demonstrated that SJL/J mice were protected from steatosis because their heart and skeletal muscle took up and oxidized twice as much FA as compared with C57BL/6J mice. As a result of this muscle diversion, serum-free FA and ketone bodies rose much less after fasting in SJL/J mice as compared with C57BL/6J mice. When livers of SJL/J and C57BL/6J mice were perfused with similar concentrations of FA, the livers took up and esterified similar amounts. We conclude that SJL/J mice express one or more variant genes that lead to enhanced FA uptake and oxidation in muscle, thereby sparing the liver from FA overload in the fasting state.

Genes & Development, 2005

Peroxisome proliferator-activated receptor ␥ (PPAR␥) is the master regulator of adipogenesis as w... more Peroxisome proliferator-activated receptor ␥ (PPAR␥) is the master regulator of adipogenesis as well as the target of thiazolidinedione (TZD) antidiabetic drugs. Many PPAR␥ target genes are induced during adipogenesis, but others, such as glycerol kinase (GyK), are expressed at low levels in adipocytes and dramatically up-regulated by TZDs. Here, we have explored the mechanism whereby an exogenous PPAR␥ ligand is selectively required for adipocyte gene expression. The GyK gene contains a functional PPAR␥-response element to which endogenous PPAR␥ is recruited in adipocytes. However, unlike the classic PPAR␥-target gene aP2, which is constitutively associated with coactivators, the GyK gene is targeted by nuclear receptor corepressors in adipocytes. TZDs trigger the dismissal of corepressor histone deacetylase (HDAC) complexes and the recruitment of coactivators to the GyK gene. TZDs also induce PPAR␥-Coactivator 1␣ (PGC-1␣), whose recruitment to the GyK gene is sufficient to release the corepressors. Thus, selective modulation of adipocyte PPAR␥ target genes by TZDs involves the dissociation of corepressors by direct and indirect mechanisms. ; FAX (215) 898-5408. Article published online ahead of print. Article and publication date are at http://www.genesdev.org/cgi/

Cell Metabolism, 2005

The high-cholesterol/high-fat Western diet has abetted an epidemic of atherosclerotic cardiovascu... more The high-cholesterol/high-fat Western diet has abetted an epidemic of atherosclerotic cardiovascular disease, the leading cause of death in industrialized nations. Liver X receptors (LXRs) are oxysterol sensors that are required for normal cholesterol and triglyceride homeostasis, yet synthetic LXR agonists produce undesirable hypertriglyceridemia. Here we report a previously unrecognized role for hepatic LXR␣ in the links between diet, serum lipids, and atherosclerosis. A modest increase in hepatic LXR␣ worsened serum lipid profiles in LDL-receptor null mice fed normal chow but had the opposite effect on lipids and afforded strong protection against atherosclerosis on a Western diet. The beneficial effect of hepatic LXR␣ was abrogated by a synthetic LXR agonist, which activated SREBP-1c and its target genes. Thus, the interplay between diet and hepatic LXR␣ is a critical determinant of serum lipid profiles and cardiovascular risk, and selective modulation of LXR target genes in liver can ameliorate hyperlipidemia and cardiovascular disease. CELL METABOLISM : MAY

AJP: Endocrinology and Metabolism, 2007

Peroxisome proliferator-activated receptor-γ (PPARγ) regulates adipocyte genes involved in adipog... more Peroxisome proliferator-activated receptor-γ (PPARγ) regulates adipocyte genes involved in adipogenesis and lipid metabolism and is the molecular target for thiazolidinedione (TZD) antidiabetic agents. Adipose triglyceride lipase (ATGL) is a recently described triglyceride-specific lipase that is induced during adipogenesis and remains highly expressed in mature adipocytes. This study evaluates the ability of PPARγ to directly regulate ATGL expression in adipocytes in vitro and in vivo. In fully differentiated 3T3-L1 adipocytes, ATGL mRNA and protein are increased by TZD and non-TZD PPARγ agonists in a dose-and time-dependent manner. Rosiglitazone-mediated induction of ATGL mRNA is rapid and is not inhibited by the protein synthesis inhibitor cycloheximide, indicating that intervening protein synthesis is not required for this effect. Rosiglitazone-mediated induction of ATGL mRNA and protein is inhibited by the PPARγ-specific antagonist GW-9662 and is also significantly reduced following siRNA-mediated knockdown of PPARγ, supporting the direct transcriptional regulation of ATGL by PPARγ. In vivo, ATGL mRNA and protein are increased by rosiglitazone treatment in white and brown adipose tissue of mice with and without obesity due to high-fat diet or leptin deficiency. Thus, PPARγ positively regulates ATGL mRNA and protein expression in mature adipocytes in vitro and in adipose tissue in vivo, suggesting a role for ATGL in mediating PPARγ's effects on lipid metabolism.

Journal of lipid research, Jan 15, 2015

Glucagon and insulin have opposing action in governing glucose homeostasis. In type 2 diabetes (T... more Glucagon and insulin have opposing action in governing glucose homeostasis. In type 2 diabetes (T2DM) plasma glucagon is characteristically elevated, contributing to increased gluconeogenesis and hyperglycemia. Therefore, glucagon receptor antagonism has been proposed as a pharmacologic approach to treat T2DM. In support of this concept, a potent small-molecule glucagon receptor antagonist (GRA), MK-0893 for 12 weeks demonstrated in T2DM dose-dependent efficacy to reduce hyperglycemia, with an HbA1c reduction of 1.5% at the 80 mg dose. However, GRA treatment was associated with dose-dependent elevation of plasma LDL-cholesterol (LDL-c). The current studies investigated the cause for increased LDL-c. We report findings that link MK-0893 with increased GLP-2, bile acid production, and most importantly, with a robust increase of cholesterol absorption. There was not however, a GRA related modulation of cholesterol synthesis. These findings were replicated using structurally diverse GRA...

American journal of physiology. Endocrinology and metabolism, 2007

Peroxisome proliferator-activated receptor-gamma (PPARgamma) regulates adipocyte genes involved i... more Peroxisome proliferator-activated receptor-gamma (PPARgamma) regulates adipocyte genes involved in adipogenesis and lipid metabolism and is the molecular target for thiazolidinedione (TZD) antidiabetic agents. Adipose triglyceride lipase (ATGL) is a recently described triglyceride-specific lipase that is induced during adipogenesis and remains highly expressed in mature adipocytes. This study evaluates the ability of PPARgamma to directly regulate ATGL expression in adipocytes in vitro and in vivo. In fully differentiated 3T3-L1 adipocytes, ATGL mRNA and protein are increased by TZD and non-TZD PPARgamma agonists in a dose- and time-dependent manner. Rosiglitazone-mediated induction of ATGL mRNA is rapid and is not inhibited by the protein synthesis inhibitor cycloheximide, indicating that intervening protein synthesis is not required for this effect. Rosiglitazone-mediated induction of ATGL mRNA and protein is inhibited by the PPARgamma-specific antagonist GW-9662 and is also signi...

The Journal of clinical investigation, 2005

In addition to its role in energy storage, adipose tissue also accumulates cholesterol. Concentra... more In addition to its role in energy storage, adipose tissue also accumulates cholesterol. Concentrations of cholesterol and triglycerides are strongly correlated in the adipocyte, but little is known about mechanisms regulating cholesterol metabolism in fat cells. Here we report that antidiabetic thiazolidinediones (TZDs) and other ligands for the nuclear receptor PPARgamma dramatically upregulate oxidized LDL receptor 1 (OLR1) in adipocytes by facilitating the exchange of coactivators for corepressors on the OLR1 gene in cultured mouse adipocytes. TZDs markedly stimulate the uptake of oxidized LDL (oxLDL) into adipocytes, and this requires OLR1. Increased OLR1 expression, resulting either from TZD treatment or adenoviral gene delivery, significantly augments adipocyte cholesterol content and enhances fatty acid uptake. OLR1 expression in white adipose tissue is increased in obesity and is further induced by PPARgamma ligand treatment in vivo. Serum oxLDL levels are decreased in both ...

Acta neuropathologica, 2003

Mutations in the gene encoding alpha-synuclein (alpha-syn) have recently been linked to rare here... more Mutations in the gene encoding alpha-synuclein (alpha-syn) have recently been linked to rare hereditary forms of Parkinson's disease. A yeast two-hybrid screen with alpha-synuclein (alpha-syn) identified synphilin as an alpha-syn-interacting protein, potentially implicating synphilin in the pathogenesis of synucleinopathies. Co-transfection of synphilin and the central (NAC) region of alpha-syn in HEH293 cells resulted in synuclein inclusions. Furthermore, synphilin immunoreactivity has been observed in Lewy bodies (LBs) and glial cytoplasmic inclusions of synucleinopathies. To further characterize synphilin, we utilized two new anti-synphilin antibodies for biochemical and immunohistochemical studies in normal and disease brain tissues. In normal brain tissue, synphilin localized predominantly to large neurons, such as substantia nigra neurons, hippocampal pyramidal and cerebellar Purkinje cells. However, in a few pathological cases synphilin immunoreactivity was present in gli...

The Journal of Lipid Research, 2013

Hepatic glucose overproduction is a major characteristic of type 2 diabetes. Because glucagon is ... more Hepatic glucose overproduction is a major characteristic of type 2 diabetes. Because glucagon is a key regulator for glucose homeostasis, antagonizing the glucagon receptor (GCGR) is a possible therapeutic strategy for the treatment of diabetes mellitus. To study the effect of hepatic GCGR inhibition on the regulation of lipid metabolism, we generated siRNA-mediated GCGR knockdown (si-GCGR) in the db/db mouse. The hepatic knockdown of GCGR markedly reduced plasma glucose levels; however, total plasma cholesterol was increased. The detailed lipid analysis showed an increase in the LDL fraction, and no change in VLDL HDL fractions. Further studies showed that the increase in LDL was the result of over-expression of hepatic lipogenic genes and elevated de novo lipid synthesis. Inhibition of hepatic glucagon signaling via siRNA-mediated GCGR knockdown had an effect on both glucose and lipid metabolism in db/db mice.

Journal of Clinical Investigation, 2005

In addition to its role in energy storage, adipose tissue also accumulates cholesterol. Concentra... more In addition to its role in energy storage, adipose tissue also accumulates cholesterol. Concentrations of cholesterol and triglycerides are strongly correlated in the adipocyte, but little is known about mechanisms regulating cholesterol metabolism in fat cells. Here we report that antidiabetic thiazolidinediones (TZDs) and other ligands for the nuclear receptor PPARγ dramatically upregulate oxidized LDL receptor 1 (OLR1) in adipocytes by facilitating the exchange of coactivators for corepressors on the OLR1 gene in cultured mouse adipocytes. TZDs markedly stimulate the uptake of oxidized LDL (oxLDL) into adipocytes, and this requires OLR1. Increased OLR1 expression, resulting either from TZD treatment or adenoviral gene delivery, significantly augments adipocyte cholesterol content and enhances fatty acid uptake. OLR1 expression in white adipose tissue is increased in obesity and is further induced by PPARγ ligand treatment in vivo. Serum oxLDL levels are decreased in both lean and obese diabetic animals treated with TZDs. These data identify OLR1 as a novel PPARγ target gene in adipocytes. While the physiological role of adipose tissue in cholesterol and oxLDL metabolism remains to be established, the induction of OLR1 is a potential means by which PPARγ ligands regulate lipid metabolism and insulin sensitivity in adipocytes.

Journal of Biological Chemistry, 2009

The accumulation of triglycerides (TG) in the liver, designated hepatic steatosis, is characteris... more The accumulation of triglycerides (TG) in the liver, designated hepatic steatosis, is characteristically associated with obesity and insulin resistance, but it can also develop after fasting. Here, we show that fasting-induced hepatic steatosis is under genetic control in inbred mice. After a 24-h fast, C57BL/6J mice and SJL/J mice both lost more than 20% of body weight and approximately 60% of total body TG. In C57BL/6J mice, TG accumulated in liver, producing frank steatosis. In striking contrast, SJL/J mice failed to accumulate any hepatic TG even though they lost nearly as much adipose tissue mass as the C57BL/6J mice. Mice from five other inbred strains developed fasting-induced steatosis like the C57BL/6J mice. Measurements of the uptake of free fatty acids (FA) in vivo and in vitro demonstrated that SJL/J mice were protected from steatosis because their heart and skeletal muscle took up and oxidized twice as much FA as compared with C57BL/6J mice. As a result of this muscle diversion, serum-free FA and ketone bodies rose much less after fasting in SJL/J mice as compared with C57BL/6J mice. When livers of SJL/J and C57BL/6J mice were perfused with similar concentrations of FA, the livers took up and esterified similar amounts. We conclude that SJL/J mice express one or more variant genes that lead to enhanced FA uptake and oxidation in muscle, thereby sparing the liver from FA overload in the fasting state.

Genes & Development, 2005

Peroxisome proliferator-activated receptor ␥ (PPAR␥) is the master regulator of adipogenesis as w... more Peroxisome proliferator-activated receptor ␥ (PPAR␥) is the master regulator of adipogenesis as well as the target of thiazolidinedione (TZD) antidiabetic drugs. Many PPAR␥ target genes are induced during adipogenesis, but others, such as glycerol kinase (GyK), are expressed at low levels in adipocytes and dramatically up-regulated by TZDs. Here, we have explored the mechanism whereby an exogenous PPAR␥ ligand is selectively required for adipocyte gene expression. The GyK gene contains a functional PPAR␥-response element to which endogenous PPAR␥ is recruited in adipocytes. However, unlike the classic PPAR␥-target gene aP2, which is constitutively associated with coactivators, the GyK gene is targeted by nuclear receptor corepressors in adipocytes. TZDs trigger the dismissal of corepressor histone deacetylase (HDAC) complexes and the recruitment of coactivators to the GyK gene. TZDs also induce PPAR␥-Coactivator 1␣ (PGC-1␣), whose recruitment to the GyK gene is sufficient to release the corepressors. Thus, selective modulation of adipocyte PPAR␥ target genes by TZDs involves the dissociation of corepressors by direct and indirect mechanisms. ; FAX (215) 898-5408. Article published online ahead of print. Article and publication date are at http://www.genesdev.org/cgi/

Cell Metabolism, 2005

The high-cholesterol/high-fat Western diet has abetted an epidemic of atherosclerotic cardiovascu... more The high-cholesterol/high-fat Western diet has abetted an epidemic of atherosclerotic cardiovascular disease, the leading cause of death in industrialized nations. Liver X receptors (LXRs) are oxysterol sensors that are required for normal cholesterol and triglyceride homeostasis, yet synthetic LXR agonists produce undesirable hypertriglyceridemia. Here we report a previously unrecognized role for hepatic LXR␣ in the links between diet, serum lipids, and atherosclerosis. A modest increase in hepatic LXR␣ worsened serum lipid profiles in LDL-receptor null mice fed normal chow but had the opposite effect on lipids and afforded strong protection against atherosclerosis on a Western diet. The beneficial effect of hepatic LXR␣ was abrogated by a synthetic LXR agonist, which activated SREBP-1c and its target genes. Thus, the interplay between diet and hepatic LXR␣ is a critical determinant of serum lipid profiles and cardiovascular risk, and selective modulation of LXR target genes in liver can ameliorate hyperlipidemia and cardiovascular disease. CELL METABOLISM : MAY

AJP: Endocrinology and Metabolism, 2007

Peroxisome proliferator-activated receptor-γ (PPARγ) regulates adipocyte genes involved in adipog... more Peroxisome proliferator-activated receptor-γ (PPARγ) regulates adipocyte genes involved in adipogenesis and lipid metabolism and is the molecular target for thiazolidinedione (TZD) antidiabetic agents. Adipose triglyceride lipase (ATGL) is a recently described triglyceride-specific lipase that is induced during adipogenesis and remains highly expressed in mature adipocytes. This study evaluates the ability of PPARγ to directly regulate ATGL expression in adipocytes in vitro and in vivo. In fully differentiated 3T3-L1 adipocytes, ATGL mRNA and protein are increased by TZD and non-TZD PPARγ agonists in a dose-and time-dependent manner. Rosiglitazone-mediated induction of ATGL mRNA is rapid and is not inhibited by the protein synthesis inhibitor cycloheximide, indicating that intervening protein synthesis is not required for this effect. Rosiglitazone-mediated induction of ATGL mRNA and protein is inhibited by the PPARγ-specific antagonist GW-9662 and is also significantly reduced following siRNA-mediated knockdown of PPARγ, supporting the direct transcriptional regulation of ATGL by PPARγ. In vivo, ATGL mRNA and protein are increased by rosiglitazone treatment in white and brown adipose tissue of mice with and without obesity due to high-fat diet or leptin deficiency. Thus, PPARγ positively regulates ATGL mRNA and protein expression in mature adipocytes in vitro and in adipose tissue in vivo, suggesting a role for ATGL in mediating PPARγ's effects on lipid metabolism.

Journal of lipid research, Jan 15, 2015

Glucagon and insulin have opposing action in governing glucose homeostasis. In type 2 diabetes (T... more Glucagon and insulin have opposing action in governing glucose homeostasis. In type 2 diabetes (T2DM) plasma glucagon is characteristically elevated, contributing to increased gluconeogenesis and hyperglycemia. Therefore, glucagon receptor antagonism has been proposed as a pharmacologic approach to treat T2DM. In support of this concept, a potent small-molecule glucagon receptor antagonist (GRA), MK-0893 for 12 weeks demonstrated in T2DM dose-dependent efficacy to reduce hyperglycemia, with an HbA1c reduction of 1.5% at the 80 mg dose. However, GRA treatment was associated with dose-dependent elevation of plasma LDL-cholesterol (LDL-c). The current studies investigated the cause for increased LDL-c. We report findings that link MK-0893 with increased GLP-2, bile acid production, and most importantly, with a robust increase of cholesterol absorption. There was not however, a GRA related modulation of cholesterol synthesis. These findings were replicated using structurally diverse GRA...