Glucagon regulates hepatic lipid metabolism via cAMP and Insig-2 signaling: implication for the pathogenesis of hypertriglyceridemia and hepatic steatosis

Wang, Hai; Zhao, Man; Sud, Neetu; Christian, Patricia J.; Shen, Jing; Song, Yaping; Pashaj, Anjeza; Zhang, Kezhong; Carr, Timothy P.; Su, Qiaozhu

doi:10.1038/srep32246

Cited by 36 publications

(34 citation statements)

References 42 publications

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“…Activated CREB also stimulates expression of the nuclear hormone receptor coactivator known as peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α), which upregulates gluconeogenic genes as well as genes involved in mitochondrial fatty acid oxidation [54]. Additionally, a recent study reported that CREB can also regulate the activity of sterol regulatory element-binding protein-1c (SREBP-1c), a transcription factor for lipogenic genes involved in de novo hepatic lipogenesis, such as fatty acid synthase, through the insulin induced gene-2 (Insig-2) [55]. The outcomes of PKA activation in the liver are summarized in Fig.…”

Section: Introductionmentioning

confidence: 99%

Role of cAMP and phosphodiesterase signaling in liver health and disease

Wahlang

McClain

Barve

et al. 2018

Cellular Signalling

108

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Liver disease is a significant health problem worldwide with mortality reaching around 2 million deaths a year. Non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are the major causes of chronic liver disease. Pathologically, NAFLD and ALD share similar patterns of hepatic disorders ranging from simple steatosis to steatohepatitis, fibrosis and cirrhosis. It is becoming increasingly important to identify new pharmacological targets, given that there is no FDA-approved therapy yet for either NAFLD or ALD. Since the evolution of liver diseases is a multifactorial process, several mechanisms involving parenchymal and non-parenchymal hepatic cells contribute to the initiation and progression of liver pathologies. Moreover, certain protective molecular pathways become repressed during liver injury including signaling pathways such as the cyclic adenosine monophosphate (cAMP) pathway. cAMP, a key second messenger molecule, regulates various cellular functions including lipid metabolism, inflammation, cell differentiation and injury by affecting gene/protein expression and function. This review addresses the current understanding of the role of cAMP metabolism and consequent cAMP signaling pathway(s) in the context of liver health and disease. The cAMP pathway is extremely sophisticated and complex with specific cellular functions dictated by numerous factors such abundance, localization and degradation by phosphodiesterases (PDEs). Furthermore, because of the distinct yet divergent roles of both of its effector molecules, the cAMP pathway is extensively targeted in liver injury to modify its role from physiological to therapeutic, depending on the hepatic condition. This review also examines the behavior of the cAMP-dependent pathway in NAFLD, ALD and in other liver diseases and focuses on PDE inhibition as an excellent therapeutic target in these conditions.

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Section: Introductionmentioning

confidence: 99%

Role of cAMP and phosphodiesterase signaling in liver health and disease

Wahlang

McClain

Barve

et al. 2018

Cellular Signalling

108

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“…1) (Stark and Keller 1987, Cordoba-Chacon et al 2015, Wang et al 2016a. Growth hormone deficiency in NAFLD may contribute to hepatic steatosis by removing GH-mediated suppression of DNL.…”

Section: De Novo Lipogenesismentioning

confidence: 99%

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

Geisler

Renquist

2017

Journal of Endocrinology

156

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Fatty liver can be diet, endocrine, drug, virus or genetically induced. Independent of cause, hepatic lipid accumulation promotes systemic metabolic dysfunction. By acting as peroxisome proliferator-activated receptor (PPAR) ligands, hepatic non-esterified fatty acids upregulate expression of gluconeogenic, beta-oxidative, lipogenic and ketogenic genes, promoting hyperglycemia, hyperlipidemia and ketosis. The typical hormonal environment in fatty liver disease consists of hyperinsulinemia, hyperglucagonemia, hypercortisolemia, growth hormone deficiency and elevated sympathetic tone. These endocrine and metabolic changes further encourage hepatic steatosis by regulating adipose tissue lipolysis, liver lipid uptake, de novo lipogenesis (DNL), beta-oxidation, ketogenesis and lipid export. Hepatic lipid accumulation may be induced by 4 separate mechanisms: (1) increased hepatic uptake of circulating fatty acids, (2) increased hepatic de novo fatty acid synthesis, (3) decreased hepatic beta-oxidation and (4) decreased hepatic lipid export. This review will discuss the hormonal regulation of each mechanism comparing multiple physiological models of hepatic lipid accumulation. Nonalcoholic fatty liver disease (NAFLD) is typified by increased hepatic lipid uptake, synthesis, oxidation and export. Chronic hepatic lipid signaling through PPARgamma results in gene expression changes that allow concurrent activity of DNL and beta-oxidation. The importance of hepatic steatosis in driving systemic metabolic dysfunction is highlighted by the common endocrine and metabolic disturbances across many conditions that result in fatty liver. Understanding the mechanisms underlying the metabolic dysfunction that develops as a consequence of hepatic lipid accumulation is critical to identifying points of intervention in this increasingly prevalent disease state.

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“…Plasmas and livers were collected 10h after LPS treatment for further analysis. Tissue collections were performed at the end points of each experiment, as follows: animals were anesthetized using isoflurane (3% mixed with oxygen), tissues were excised and flash frozen in liquid nitrogen, and livers were then homogenized in solubilization buffer for further analysis as described previously [24, 25]. …”

Section: Methodsmentioning

confidence: 99%

CREBH mediates metabolic inflammation to hepatic VLDL overproduction and hyperlipoproteinemia

et al. 2017

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Metabolic inflammation is closely associated with hyperlipidemia and cardiovascular disease. However, the underlying mechanisms are not fully understood. The current study established that cAMP-responsive-element-binding protein H (CREBH), an acute-phase transcription factor, enhances very-low-density lipoprotein (VLDL) assembly and secretion by upregulating apolipoprotein B (apoB) expression, and contributes to metabolic inflammation-associated hyperlipoproteinemia induced by TNFα, lipopolysaccharides (LPS), and a high-fat diet (HFD) in mice. Specifically, overexpression of CREBH significantly induced mRNA and protein expression of apoB in McA-7777 cells. Luciferase assay further revealed that the presence of CREBH could significantly increase the activities of the apoB gene promoter. In contrast, genetic depletion of CREBH in mice resulted in significant reduction in expression of hepatic apoB mRNA. Challenging mice with an acute fat load led to upregulation of triglyceride (TG)-rich lipoprotein secretion in wildtype mice, but not in CREBH-null mice. TNFα treatment activated hepatic CREBH expression, which in turn enhanced hepatic apoB biosynthesis and VLDL secretion. Metabolic inflammation induced by LPS or HFD also resulted in overproduction of apoB and hyperlipoproteinemia in wildtype mice, but not in CREBH-null mice. This study demonstrates that CREBH could be a mediator between metabolic inflammation and hepatic VLDL overproduction in chronic metabolic disorders. This novel finding establishes CREBH as the first transcription factor that regulates apoB expression on the transcriptional level and the subsequent VLDL biosynthesis in response to metabolic inflammation. The study also provides novel insight into the pathogenesis of hyperlipidemia in metabolic syndrome.

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Glucagon regulates hepatic lipid metabolism via cAMP and Insig-2 signaling: implication for the pathogenesis of hypertriglyceridemia and hepatic steatosis

Cited by 36 publications

References 42 publications

Role of cAMP and phosphodiesterase signaling in liver health and disease

Role of cAMP and phosphodiesterase signaling in liver health and disease

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

CREBH mediates metabolic inflammation to hepatic VLDL overproduction and hyperlipoproteinemia

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