Chronic activation of AMPK limits hepatic triglyceride accumulation independent of changes in total glycerol‐3‐phosphate‐acyltransferase activity

Background: Tamoxifen (TMX) has proven to be effective in the prevention and treatment of breast cancer. However, long-term use of TMX is associated with hepatic steatosis, oxidative liver injury and hepatocarcinoma. Buchholzia coriacea seeds (BCS) have been widely applied in traditional medicine due to their nutritional and therapeutic potentials. This study investigates the protective effect of hydroethanolic extract of (defatted) B. coriacea seeds (HEBCS) against TMX–induced hepatotoxicity in rats. Methods: Thirty-six (36) male albino rats were divided into six groups (n = 6/group). Group I served as control. Group II received 50 mg/kg/day TMX orally (p.o.) (TMX) for 21 days, group III received TMX plus 125 mg/kg/d HEBCS p.o. (HEBCS 125) for 21 days, group IV received TMX plus 250 mg/kg/d HEBCS p.o. (HEBCS 250) for 21 days and rats in group V and VI received HEBCS 125 and HEBCS 250 respectively for 21 days. Results: Compared with the control, TMX caused a significant increase (p < 0.05) in serum hepatic function biomarkers: alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase by 57%, 60% and 68% respectively. TMX also caused a significant increase in hepatic triglycerides level by 166% when compared with control and a significant decrease in serum HDL-cholesterol level by 37%. Compared with control, hepatic marker of inflammation, tumour necrosis factor alpha (TNF-α) increased significantly by 220%, coupled with significant increase in expression of interleukin 6 and cyclooxygenase 2. There was also significant increase in levels of Biomarkers of oxidative stress, nitric oxide, malondialdehyde and protein carbonyls in the TMX group by 89%, 175% and 114% respectively when compared with the control. Hepatic antioxidants, reduced glutathione (GSH) level and activities of superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST) and glutathione peroxidase (GSH-Px) decreased significantly in the TMX group by 35%, 67%, 41%, 59% and 53% respectively when compared with the control. However, HEBCS at 250 mg/kg significantly protected against TMX–induced hepatotoxicity by decreasing hepatic triglyceride content, serum hepatic function biomarkers, hepatic inflammation and oxidative stress with significant improvement in hepatic antioxidant system. Histopathological findings show that HEBCS alleviate TMX–induced hepatocyte ballooning. Conclusions: Current data suggest that HEBCS protected against TMX–induced hepatotoxicity in rats. HEBCS may be useful in managing TMX–induced toxicities in breast cancer patients. It may also be helpful against other forms of liver injury involving steatosis, inflammation, free radicals, and oxidative damage.

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Kaempferol reduces hepatic triglyceride accumulation by inhibiting Akt

Journal of Food Biochemistry ◽

10.1111/jfbc.13034 ◽

2019 ◽

Vol 43 (11) ◽

Cited By ~ 4

Author(s):

Minh‐Hien Hoang ◽

Yaoyao Jia ◽

Ji Hae Lee ◽

Yeonji Kim ◽

Sung‐Joon Lee

Keyword(s):

Hepatic Triglyceride ◽

Triglyceride Accumulation

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Interactions of insulin, glucagon and dexamethasone in controlling the activity of glycerol phosphate acyltransferase and the activity and subcellular distribution of phosphatidate phosphohydrolase in cultured rat hepatocytes

Biochemical Journal ◽

10.1042/bj2300525 ◽

1985 ◽

Vol 230 (2) ◽

pp. 525-534 ◽

Cited By ~ 40

Author(s):

R A Pittner ◽

R Fears ◽

D N Brindley

Keyword(s):

Neutral Lipids ◽

Relative Proportion ◽

Rat Hepatocytes ◽

Glycerol Phosphate ◽

Acyltransferase Activity ◽

Phosphatidate Phosphohydrolase ◽

Cultured Rat Hepatocytes ◽

Total Glycerol

Rat hepatocytes were incubated in monolayer culture for 8 h. Glucagon (10nM) increased the total phosphatidate phosphohydrolase activity by 1.7-fold. This effect was abolished by adding cycloheximide, actinomycin D or 500 pM-insulin to the incubations. The glucagon-induced increase was synergistic with that produced by an optimum concentration of 100 nM-dexamethasone. Theophylline (1mM) potentiated the effect of glucagon, but it did not affect the dexamethasone-induced increase in the phosphohydrolase activity. The relative proportion of the phosphohydrolase activity associated with membranes was decreased by glucagon when 0.15 mM-oleate was added 15 min before the end of the incubations to translocate the phosphohydrolase from the cytosol. This glucagon effect was not seen at 0.5 mM-oleate. Since glucagon also increased the total phosphohydrolase activity, the membrane-associated activity was maintained at 0.15 mM-oleate and was increased at 0.5 mM-oleate. This activity at both oleate concentrations was also increased in incubations that contained dexamethasone, particularly in the presence of glucagon. Insulin increased the relative proportion of phosphatidate phosphohydrolase that was associated with membranes at 0.15 mM-oleate, but not at 0.5 mM-oleate. It also decreased the absolute phosphohydrolase activity on the membranes at both oleate concentrations in incubations that also contained glucagon and dexamethasone. None of the hormonal combinations significantly altered the total glycerol phosphate acyltransferase activity. However, glucagon significantly increased the microsomal activities, and insulin had the opposite effect. Glucagon also decreased the mitochondrial acyltransferase activity. There was a highly significant correlation between the total phosphatidate phosphohydrolase activity and the synthesis of neutral lipids from glycerol phosphate and 0.5 mM-oleate in homogenates of cells from all of the hormonal combinations. Phosphatidate phosphohydrolase activity is increased in the long term by glucocorticoids and also by glucagon through cyclic AMP. In the short term, glucagon increases the concentration of fatty acid required to translocate the cytosolic reservoir of activity to the membranes on which phosphatidate is synthesized. Insulin opposes the combined actions of glucagon and glucocorticoids. The long-term events explain the large increases in the phosphohydrolase activity that occur in vivo in a variety of stress conditions. The expression of this activity depends on increases in the net availability of fatty acids and their CoA esters in the liver.

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Liver-specific deletion of acetyl-CoA carboxylase 1 reduces hepatic triglyceride accumulation without affecting glucose homeostasis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0603115103 ◽

2006 ◽

Vol 103 (22) ◽

pp. 8552-8557 ◽

Cited By ~ 173

Author(s):

J. Mao ◽

F. J. DeMayo ◽

H. Li ◽

L. Abu-Elheiga ◽

Z. Gu ◽

...

Keyword(s):

Glucose Homeostasis ◽

Acetyl Coa Carboxylase ◽

Hepatic Triglyceride ◽

Acetyl Coa ◽

Triglyceride Accumulation ◽

Specific Deletion

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Essential fatty acid deficiency and plasma triglyceride turnover in rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1980.238.5.e499 ◽

1980 ◽

Vol 238 (5) ◽

pp. E499-E505 ◽

Cited By ~ 1

Author(s):

M. T. Huang ◽

M. A. Williams

Keyword(s):

Fatty Acid ◽

Essential Fatty Acid ◽

Essential Fatty Acid Deficiency ◽

Plasma Triglyceride ◽

Hepatic Triglyceride ◽

Triglyceride Accumulation ◽

Essential Fatty Acid Deficient ◽

Triglyceride Secretion ◽

Acid Deficiency ◽

Fatty Acid Deficiency

Hepatic triglyceride secretion in essential fatty acid-deficient rats was examined by three separate techniques in an effort to resolve conflicting evidence on the question of whether essential fatty acid deficiency altered hepatic triglyceride secretion in vivo. First, plasma triglyceride turnover was measured by intravenous injection of [2-3H]glycerol trioleate. Equations of the kinetics were formulated based on a single, open pool model. Turnover rates and pool sizes of plasma triglyceride were calculated from these equations. Second, [2-3H]glycerol was injected, and apparent rate constants for plasma triglyceride secretion and clearance were calculated by kinetic analysis. Third, Triton WR-1339 was used to inhibit lipoprotein clearance from blood plasma, and rates of plasma triglyceride accumulation were measured. The results of these studies showed that the rate of hepatic triglyceride secretion was 2-3 times greater in essential fatty acid-deficient rats than in nondeficient controls. The increase in triglyceride secretion, as well as the higher level of liver triglyceride typical of essential fatty acid-deficient rats, could be caused by increased lipogenesis and increased mobilization of fatty acids from adipose tissues.

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