Regulation of Hepatic Lipin-1 by Ethanol: Role of AMP-Activated Protein Kinase/Sterol Regulatory Element-Binding Protein 1 Signaling in Mice

Hu, Ming; Wang, Fengming; Li, Xin; Rogers, Christopher Q.; Liang, Xiaomei; Finck, Brian N.; Mitra, Mayurranjan S.; Zhang, Ray; Mitchell, Dave A.; You, Min

doi:10.1002/hep.24708

Cited by 115 publications

(148 citation statements)

References 27 publications

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“…24 Recombinant LCN2 induced a significant, concentration-dependent increase in the TGs contents of AML-12 hepatocytes ( Figure 1A and Supplemental Figure S1A …”

Section: Lcn2 Regulates Ethanol-induced Cellular Lipid Accumulation Imentioning

confidence: 99%

“…24 For pGL3-24p3/LCN2-Luciferase reporter assays, plasmids were transiently transfected into AML-12 hepatocytes by Lipofectamine reagent for 48 hours. Luciferase assays were performed with cell extracts, and the results were averaged to represent a single data point for each transfection.…”

Section: Measurement Of Intracellular Tgmentioning

confidence: 99%

“…19,22,24,25 Lcn2KO mice were on the C57BL/6 background and phenotypically normal under a chow diet. 13 Ethanol feeding to WT mice significantly increased the levels of LCN2 mRNA expression to approximately 145% of WT controls and serum LCN2 levels to approximately 200% of WT controls (Supplemental Figure S1B and Figure 2A), respectively.…”

Section: Deletion Of Lcn2 Partially Ameliorates Ethanolinduced Fatty mentioning

confidence: 99%

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The Detrimental Role Played by Lipocalin-2 in Alcoholic Fatty Liver in Mice

Cai

Jogasuria

Yin

et al. 2016

The American Journal of Pathology

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We have previously shown that the ethanol-mediated elevation of lipocaline-2 (LCN2) is closely associated with the development of alcoholic fatty liver disease (AFLD) in mice. Herein, we aimed to understand the functional significance of LCN2 induction by ethanol and to explore its underlying mechanisms. We evaluated the effects of LCN2 in an in vitro cellular alcoholic steatosis model and in an animal study using wild-type and LCN2 knockout mice fed for 4 weeks with an ethanol-supplemented Lieber-DeCarli diet. In the cellular model of alcoholic steatosis, recombinant LCN2 or overexpression of LCN2 exacerbated ethanol-induced fat accumulation, whereas knocking down LCN2 prevented steatosis in hepatocytes exposed to ethanol. Consistently, removal of LCN2 partially but significantly alleviated alcoholic fatty liver injury in mice. Mechanistically, LCN2 mediates detrimental effects of ethanol in the liver via disrupted multiple signaling pathways, including aberrant nicotinamide phosphoribosyltransferaseesirtuin 1 axis, perturbed endocrine metabolic regulatory fibroblast growth factor 15/19 signaling, and impaired chaperone-mediated autophagy. Finally, compared with healthy human livers, liver samples from patients with AFLD had lower gene expression of several LCN2-regualted molecules. Our study demonstrated a pivotal and causal role of LCN2 in the development of AFLD and suggested that targeting the LCN2 could be of great value for the treatment of human AFLD. (Am J Pathol 2016 http://dx

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“…24 Recombinant LCN2 induced a significant, concentration-dependent increase in the TGs contents of AML-12 hepatocytes ( Figure 1A and Supplemental Figure S1A …”

Section: Lcn2 Regulates Ethanol-induced Cellular Lipid Accumulation Imentioning

confidence: 99%

Section: Measurement Of Intracellular Tgmentioning

confidence: 99%

Section: Deletion Of Lcn2 Partially Ameliorates Ethanolinduced Fatty mentioning

confidence: 99%

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The Detrimental Role Played by Lipocalin-2 in Alcoholic Fatty Liver in Mice

Cai

Jogasuria

Yin

et al. 2016

The American Journal of Pathology

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“…The SREBP1c-induced increase in ACC activity directly increases fatty acid synthesis, while suppressing fatty acid oxidation. SREBP1c also upregulates lipin-1 expression and localization to the cytosol (Hu et al 2012). Within the cytosol, lipin-1 acts as a phosphatidate phosphatase, enzymatically converting phosphatidate to diacylglycerol and promoting triglyceride synthesis.…”

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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“…This inhibition plays a key role in the development of steatosis by the activation of hepatic lipogenesis, cholesterol synthesis, and glucose production in parallel with the decrease in fatty acid oxidation [74] . In rat hepatoma cells, overexpression of a constitutively active form of AMPK blocked the effect of ethanol, but in contrast, a dominant negative form augmented the effect through regulating SREBP-1 [77] . Recent data have demonstrated that Lipin-1, a Mg 2+ phosphatidate phosphatase involved in the biosynthesis of triacylglycerol and the transcriptional regulation of lipid homeostasis, is upregulated by ethanol through inhibition of AMPK and activation of SREBP-1 [78] .…”

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confidence: 93%

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

Ceni

Mello

Galli

2014

WJG

415

339

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Alcohol consumption is a predominant etiological factor in the pathogenesis of chronic liver diseases, resulting in fatty liver, alcoholic hepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma (HCC). Although the pathogenesis of alcoholic liver disease (ALD) involves complex and still unclear biological processes, the oxidative metabolites of ethanol such as acetaldehyde and reactive oxygen species (ROS) play a preeminent role in the clinical and pathological spectrum of ALD. Ethanol oxidative metabolism influences intracellular signaling pathways and deranges the transcriptional control of several genes, leading to fat accumulation, fibrogenesis and activation of innate and adaptive immunity. Acetaldehyde is known to be toxic to the liver and alters lipid homeostasis, decreasing peroxisome proliferator-activated receptors and increasing sterol regulatory element binding protein activity via an AMP-activated protein kinase (AMPK)-dependent mechanism. AMPK activation by ROS modulates autophagy, which has an important role in removing lipid droplets. Acetaldehyde and aldehydes generated from lipid peroxidation induce collagen synthesis by their ability to form protein adducts that activate transforming-growth-factor-β-dependent and independent profibrogenic pathways in activated hepatic stellate cells (HSCs). Furthermore, activation of innate and adaptive immunity in response to ethanol metabolism plays a key role in the development and progression of ALD. Acetaldehyde alters the intestinal barrier and promote lipopolysaccharide (LPS) translocation by disrupting tight and adherent junctions in human colonic mucosa. Acetaldehyde and LPS induce Kupffer cells to release ROS and proinflammatory cytokines and chemokines that contribute to neutrophils infiltration. In addition, alcohol consumption inhibits natural killer cells that are cytotoxic to HSCs and thus have an important antifibrotic function in the liver. Ethanol metabolism may also interfere with cell-mediated adaptive immunity by impairing proteasome function in macrophages and dendritic cells, and consequently alters allogenic antigen presentation. Finally, acetaldehyde and ROS have a role in alcohol-related carcinogenesis because they can form DNA adducts that are prone to mutagenesis, and they interfere with methylation, synthesis and repair of DNA, thereby increasing HCC susceptibility. Key words: Alcohol metabolism; Acetaldehyde; Reactive oxygen species; Alcoholic liver disease; Protein adducts; Hepatic stellate cells; Liver fibrosis; CYP2E1Core tip: The goal of this article is to review the mechanisms of alcohol-mediated toxicity in parenchymal and non-parenchymal cells of the liver. Specifically, we highlight the effect of oxidative ethanol metabolites such as acetaldehyde and reactive oxygen species in the development of fat accumulation, fibrosis and deranged immune response.Ceni E, Mello T, Galli A. Pathogenesis of alcoholic liver disease: Role of oxidative metabolism.

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Regulation of Hepatic Lipin-1 by Ethanol: Role of AMP-Activated Protein Kinase/Sterol Regulatory Element-Binding Protein 1 Signaling in Mice

Cited by 115 publications

References 27 publications

The Detrimental Role Played by Lipocalin-2 in Alcoholic Fatty Liver in Mice

The Detrimental Role Played by Lipocalin-2 in Alcoholic Fatty Liver in Mice

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

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