Central role of PPARα-dependent hepatic lipid turnover in dietary steatohepatitis in mice

Excessive lipid deposition is a hallmark of NAFLD. Although much has been learned about the enzymes and metabolites involved in NAFLD, few studies have focused on the role of long noncoding RNAs (lncRNAs) in hepatic lipid accumulation. Here, using in vitro and in vivo models of NAFLD, we found that the lncRNA Gm15622 is highly expressed in the liver of obese mice fed a HFD and in murine liver (AML-12) cells treated with free fatty acids. Investigating the molecular mechanism in the liver-enriched expression of Gm15622 and its effects on lipid accumulation in hepatocytes and on NAFLD pathogenesis, we found that Gm15622 acts as a sponge for the microRNA miR-742-3p. This sponging activity increased the expression of the transcriptional regulator SREBP-1c and promoted lipid accumulation in the liver of the HFD mice and AML-12 cells. Moreover, further results indicated that metformin suppresses Gm15622 and alleviates NAFLD-associated lipid deposition in mice. In conclusion, we have identified an lncRNA Gm15622/miR-742-3p/SREBP-1c regulatory circuit associated with NAFLD in mice, a finding that significantly advances our insight into how lipid metabolism and accumulation are altered in this metabolic disorder. Our results also suggest that Gm15622 may be a potential therapeutic target for managing NAFLD.

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Understanding the Role of Exercise in Nonalcoholic Fatty Liver Disease: ERS-Linked Molecular Pathways

Mediators of Inflammation ◽

10.1155/2020/6412916 ◽

2020 ◽

Vol 2020 ◽

pp. 1-15

Author(s):

Yong Zou ◽

Zhengtang Qi

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Lipid Accumulation ◽

Fatty Liver Disease ◽

Molecular Pathways ◽

Nonalcoholic Fatty Liver ◽

Hepatic Lipid ◽

Hepatic Lipid Accumulation

Nonalcoholic fatty liver disease (NAFLD) is globally prevalent and characterized by abnormal lipid accumulation in the liver, frequently accompanied by insulin resistance (IR), enhanced hepatic inflammation, and apoptosis. Recent studies showed that endoplasmic reticulum stress (ERS) at the subcellular level underlies these featured pathologies in the development of NAFLD. As an effective treatment, exercise significantly reduces hepatic lipid accumulation and thus alleviates NAFLD. Confusingly, these benefits of exercise are associated with increased or decreased ERS in the liver. Further, the interaction between diet, medication, exercise types, and intensity in ERS regulation is more confusing, though most studies have confirmed the benefits of exercise. In this review, we focus on understanding the role of exercise-modulated ERS in NAFLD and ERS-linked molecular pathways. Moderate ERS is an essential signaling for hepatic lipid homeostasis. Higher ERS may lead to increased inflammation and apoptosis in the liver, while lower ERS may lead to the accumulation of misfolded proteins. Therefore, exercise acts like an igniter or extinguisher to keep ERS at an appropriate level by turning it up or down, which depends on diet, medications, exercise intensity, etc. Exercise not only enhances hepatic tolerance to ERS but also prevents the malignant development of steatosis due to excessive ERS.

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The role of the Ah locus in hexachlorobenzene-induced porphyria. Studies in congenic C57BL/6J mice

Biochemical Journal ◽

10.1042/bj2540245 ◽

1988 ◽

Vol 254 (1) ◽

pp. 245-254 ◽

Cited By ~ 31

Author(s):

M E Hahn ◽

T A Gasiewicz ◽

P Linko ◽

J A Goldstein

Keyword(s):

Urinary Excretion ◽

Causative Factor ◽

Ah Receptor ◽

Lipid Levels ◽

Uroporphyrinogen Decarboxylase ◽

Hepatic Lipid ◽

Congenic Strains ◽

Cytosolic Protein ◽

Hepatic Microsomes

The role of the Ah locus in hexachlorobenzene (HCB)-induced porphyria and the possible involvement of P-450 cytochromes P(1)450 and P(3)450 in the pathogenesis of this disease were investigated in two congenic strains of C57BL/6J mice that differ only at this locus. Female B6-Ahb mice (Ah receptor: approximately 30-70 fmol/mg of cytosolic protein) and B6-Ahd mice (Ah receptor: undetectable) were pretreated with iron (500 mg/kg) and then fed a diet containing 0 or 200 p.p.m. of HCB for up to 17 weeks. Mice from the two strains consumed similar amounts of HCB. Urinary excretion of porphyrins was increased after 7 weeks of HCB treatment in B6-Ahb mice, and after 15 weeks was over 200 times greater than that of mice given iron only. In B6-Ahd mice, porphyrin excretion did not begin to increase until after 13 weeks, and after 15 weeks was only six times greater than that of controls. Similar differences were seen in the 15-week hepatic porphyrin concentrations (B6-Ahb: 1110 +/- 393; B6-Ahd: 17.6 +/- 14.5; controls: approximately 0.20 nmol/g). Uroporphyrinogen decarboxylase (EC 4.1.1.37) activity was diminished by 70 and 20% in B6-Ahb B6-Ahd mice respectively after 15 weeks of treatment with HCB. Cytochromes P(1)450 and P(3)450 were measured in hepatic microsomes (microsomal fractions) by radioimmunoassay and immunoblotting, using antisera raised against the orthologous rat isoenzymes P450c and P450d. HCB induced small amounts of a protein recognized by anti-P450c (P(1)450) in B6-Ahd mice, but not in B6-Ahd mice. Relatively large amounts of a protein recognized by anti-P450d (P(3)450) were induced in both strains, but to a somewhat greater extent in the B6-Ahb mice. The hepatic accumulation of HCB at 15 weeks was greater in B6-Ahb than in B6-Ahd mice, in association with elevated hepatic lipid levels in the former strain. The results of this experiment indicate that the Ah locus influences the susceptibility of C57BL/6J mice to HCB-induced porphyria and are consistent with the suggestion that the sustained induction of P(3)450 and/or P(1)450 may be a causative factor in the development of this disease.

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Role of the intestinal vitamin D receptor in obesity, adipose tissue inflammation and hepatic lipid accumulation

Journal of Hepatology ◽

10.1016/s0168-8278(17)30615-3 ◽

2017 ◽

Vol 66 (1) ◽

pp. S168

Author(s):

D. Jahn ◽

D. Dorbath ◽

A.-K. Schilling ◽

L. Gildein ◽

J. Schmitt ◽

...

Keyword(s):

Vitamin D ◽

Adipose Tissue ◽

Vitamin D Receptor ◽

Lipid Accumulation ◽

Adipose Tissue Inflammation ◽

Tissue Inflammation ◽

Hepatic Lipid ◽

Hepatic Lipid Accumulation

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Hepatocyte-specificPtpn6deletion promotes hepatic lipid accretion, but reduces NAFLD in diet-induced obesity: Potential role of PPARγ

Hepatology ◽

10.1002/hep.26957 ◽

2014 ◽

Vol 59 (5) ◽

pp. 1803-1815 ◽

Cited By ~ 19

Author(s):

Elaine Xu ◽

Marie-Pier Forest ◽

Michael Schwab ◽

Rita Kohen Avramoglu ◽

Emmanuelle St-Amand ◽

...

Keyword(s):

Potential Role ◽

Hepatic Lipid ◽

Diet Induced Obesity

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111 Hepatic Lipid Partitioning and Liver Damage in NAFLD: Role of Stearoyl-CoA Desaturase

Gastroenterology ◽

10.1016/s0016-5085(08)63523-4 ◽

2008 ◽

Vol 134 (4) ◽

pp. A-754

Author(s):

Zhengzheng Li ◽

Michael P. Berk ◽

Ariel E. Feldstein

Keyword(s):

Liver Damage ◽

Hepatic Lipid ◽

Stearoyl Coa Desaturase

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Carbamoylcholine and gastrin induce inositol lipid turnover in canine gastric parietal cells

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1988.255.1.g99 ◽

1988 ◽

Vol 255 (1) ◽

pp. G99-G105 ◽

Cited By ~ 2

Author(s):

T. Chiba ◽

S. K. Fisher ◽

J. Park ◽

E. B. Seguin ◽

B. W. Agranoff ◽

...

Keyword(s):

Potential Role ◽

Inositol Phosphates ◽

Selective Reduction ◽

Parietal Cells ◽

Time Dependent ◽

Cell Uptake ◽

Inositol Phospholipids ◽

Lipid Turnover ◽

Gastric Parietal Cells

The potential role of inositol phospholipid turnover in mediating acid secretion was examined in a preparation enriched for isolated canine gastric parietal cells. The stimulatory effects of carbamoylcholine (carbachol) and gastrin on parietal cell uptake of [14C]aminopyrine were linked to dose- and time-dependent selective reduction in cellular phosphatidylinositol content, although the specific fatty acid composition of the phosphoinositides was not altered. Analysis of [3H]inositol phosphates accumulated in cells prelabeled with [3H]inositol revealed an increase in labeled inositol trisphosphate by 5 min of incubation with either carbachol or gastrin. Furthermore, after preincubation of parietal cells in medium containing [32P]orthophosphate, the two secretagogues elicited a time-dependent decrease in 32P labeling of phosphatidylinositol 4,5-bisphosphate and concomitant increase in labeling of phosphatidic acid. These data demonstrate that the acid secretagogue actions of carbachol and gastrin are correlated with turnover of cellular inositol phospholipids in a preparation consisting predominantly of parietal cells.

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