Preferential lipolysis of DGAT1 over DGAT2 generated triacylglycerol in Huh7 hepatocytes.

Two distinct diacylglycerol acyltransferases (DGAT1 and DGAT2) catalyze the final committed step of triacylglycerol (TG) synthesis in hepatocytes. After its synthesis in the endoplasmic reticulum (ER) TG is either stored in cytosolic lipid droplets (LDs) or is assembled into very low-density lipoproteins in the ER lumen. TG stored in cytosolic LDs is hydrolyzed by adipose triglyceride lipase (ATGL) and the released fatty acids are converted to energy by oxidation in mitochondria.

Attenuation of obesity-induced hyperlipidemia reduces tumor growth.

Accumulating evidence suggests that hyperlipidemia is associated with obesity and cancer mortality in humans. We tested the hypotheses that inhibition of microsomal triglyceride transfer protein (MTP) would attenuate obesity-induced hyperlipidemia and reduce tumor growth by treating BCR-ABL B cell tumor-bearing hyperlipidemic obese ob/ob obese mice with a MTP inhibitor. MTP inhibition in tumor-bearing mice reduced concentrations of plasma apoB100 5-fold together with a corresponding decrease in VLDL triacylglycerol (TG) and cholesterol.

Carboxylesterase 1d (Ces1d) does not contribute to cholesteryl ester hydrolysis in the liver.

The liver is the central organ regulating cholesterol synthesis, storage, transport, and elimination. Mouse carboxylesterase 1d (Ces1d) and its human ortholog CES1 have been described to possess lipase activity and play roles in hepatic triacylglycerol metabolism and VLDL assembly. It has been proposed that Ces1d/CES1 might also catalyze cholesteryl ester (CE) hydrolysis in the liver and thus be responsible for the hydrolysis of HDL-derived CE; this could contribute to the final step in the reverse cholesterol transport (RCT) pathway, wherein cholesterol is secreted from the liver into bile and feces, either directly or after conversion to water-soluble bile salts.

Ces1d deficiency protects against high-sucrose diet-induced hepatic triacylglycerol accumulation.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Triacylglycerol accumulation in the liver is a hallmark of NAFLD. Metabolic studies have confirmed that increased hepatic de novo lipogenesis (DNL) in humans contributes to fat accumulation in the liver and to NAFLD progression.

Fasting and refeeding induces changes in the mouse hepatic lipid droplet proteome.

Unlabelled: During fasting, the liver increases lipid storage as a mean to reserve and provide energy for vital cellular functions. After re-feeding, hepatocytes rapidly decrease the amount of triacylglycerol that is stored in lipid droplets (LDs), visible as the size of hepatic LDs significantly decreases after re-feeding. Little is known about the changes in the liver LD proteome that occur during the fasting/re-feeding transition.

Genetic variation in human carboxylesterase CES1 confers resistance to hepatic steatosis.

Obesity often leads non-alcoholic fatty liver disease, insulin resistance and hyperlipidemia. Expression of carboxylesterase CES1 is positively correlated with increased lipid storage and plasma lipid concentration. Here we investigated structural and metabolic consequences of a single nucleotide polymorphism in CES1 gene that results in p.

Loss of Calreticulin Uncovers a Critical Role for Calcium in Regulating Cellular Lipid Homeostasis.

A direct link between Ca and lipid homeostasis has not been definitively demonstrated. In this study, we show that manipulation of ER Ca causes the re-distribution of a portion of the intracellular unesterified cholesterol to a pool that is not available to the SCAP-SREBP complex. The SREBP processing pathway in ER Ca depleted cells remained fully functional and responsive to changes in cellular cholesterol status but differed unexpectedly in basal activity.

Carboxylesterases in lipid metabolism: from mouse to human.

Mammalian carboxylesterases hydrolyze a wide range of xenobiotic and endogenous compounds, including lipid esters. Physiological functions of carboxylesterases in lipid metabolism and energy homeostasis in vivo have been demonstrated by genetic manipulations and chemical inhibition in mice, and in vitro through (over)expression, knockdown of expression, and chemical inhibition in a variety of cells. Recent research advances have revealed the relevance of carboxylesterases to metabolic diseases such as obesity and fatty liver disease, suggesting these enzymes might be potential targets for treatment of metabolic disorders.

AMPK activation by GSK621 inhibits human melanoma cells in vitro and in vivo.

Recent studies suggest that forced activation of AMP-activated protein kinase (AMPK) could inhibit melanoma cell proliferation. In this report, we evaluated the anti-melanoma cell activity by a novel small-molecular AMPK activator, GSK621. Treatment of GSK621 decreased survival and proliferation of human melanoma cells (A375, WM-115 and SK-Mel-2 lines), which was accompanied by activation of caspase-3/-9 and apoptosis.

Ces3/TGH Deficiency Attenuates Steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in developed countries. NAFLD describes a wide range of liver pathologies from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. NASH is distinguished from simple steatosis by inflammation, cell death and fibrosis.

Tumor-Induced Hyperlipidemia Contributes to Tumor Growth.

The known link between obesity and cancer suggests an important interaction between the host lipid metabolism and tumorigenesis. Here, we used a syngeneic tumor graft model to demonstrate that tumor development influences the host lipid metabolism. BCR-Abl-transformed precursor B cell tumors induced hyperlipidemia by stimulating very low-density lipoprotein (VLDL) production and blunting VLDL and low-density lipoprotein (LDL) turnover.

Liver-specific expression of carboxylesterase 1g/esterase-x reduces hepatic steatosis, counteracts dyslipidemia and improves insulin signaling.

Ces1g/Es-x deficiency in mice results in weight gain, insulin resistance, fatty liver and hyperlipidemia through upregulation of de novo lipogenesis and oversecretion of triacylglycerol (TG)-rich lipoproteins. Here, we show that restoration of Ces1g/Es-x expression only in the liver significantly reduced hepatic TG concentration accompanied by decreased size of lipid droplets, reduced secretion of very low-density lipoproteins and improved insulin-mediated signal transduction in the liver. Collectively, these results demonstrate that hepatic Ces1g/Es-x plays a critical role in limiting hepatic steatosis, very low-density lipoprotein assembly and in augmenting insulin sensitivity.

Roles of Acyl-CoA:Diacylglycerol Acyltransferases 1 and 2 in Triacylglycerol Synthesis and Secretion in Primary Hepatocytes.

Objective: Very low-density lipoprotein assembly and secretion are regulated by the availability of triacylglycerol. Although compelling evidence indicates that the majority of triacylglycerol in very low-density lipoprotein is derived from re-esterification of lipolytic products released by endoplasmic reticulum-associated lipases, little is known about roles of acyl-CoA:diacylglycerol acyltransferases (DGATs) in this process. We aimed to investigate the contribution of DGAT1 and DGAT2 in lipid metabolism and lipoprotein secretion in primary mouse and human hepatocytes.

Carboxylesterase1/Esterase-x regulates chylomicron production in mice.

Elevated postprandial plasma triacylglycerol (TG) concentrations are commonly associated with obesity and the risk of cardiovascular disease. Dietary fat contributes to this condition through the production of chylomicrons. Carboxylesterases have been mainly studied for their role in drug metabolism, but recently they have been shown to participate in lipid metabolism; however, their role in intestinal lipid metabolism is unknown.

Ces3/TGH deficiency improves dyslipidemia and reduces atherosclerosis in Ldlr(-/-) mice.

Rationale: Carboxylesterase 3/triacylglycerol hydrolase (TGH) has been shown to participate in hepatic very low-density lipoprotein (VLDL) assembly. Deficiency of TGH in mice lowers plasma lipids and atherogenic lipoproteins without inducing hepatic steatosis.

Objective: To investigate the contribution of TGH to atherosclerotic lesion development in mice that lack low-density lipoprotein receptor (LDLR).

Liver specific inactivation of carboxylesterase 3/triacylglycerol hydrolase decreases blood lipids without causing severe steatosis in mice.

Unlabelled: Carboxylesterase 3/triacylglycerol hydrolase (Ces3/TGH) participates in hepatic very low-density lipoprotein (VLDL) assembly and in adipose tissue basal lipolysis. Global ablation of Ces3/Tgh expression decreases serum triacylglycerol (TG) and nonesterified fatty acid levels and improves insulin sensitivity. To understand the tissue-specific role of Ces3/TGH in lipid and glucose homeostasis, we generated mice with a liver-specific deletion of Ces3/Tgh expression (L-TGH knockout [KO]).

Lumenal lipid metabolism: implications for lipoprotein assembly.

Overproduction of apolipoprotein B (apoB)-containing lipoproteins by the liver and the intestine is 1 of the hallmarks of insulin resistance and type 2 diabetes and a well-established risk factor of cardiovascular disease. The assembly of apoB lipoproteins is regulated by the availability of lipids that form the neutral lipid core (triacylglycerol and cholesteryl ester) and the limiting lipoprotein monolayer (phospholipids and cholesterol). Although tremendous advances have been made over the past decade toward understanding neutral lipid and phospholipid biosynthesis and neutral lipid storage in cytosolic lipid droplets (LDs), little is known about the mechanisms that govern the transfer of lipids to the lumen of the endoplasmic reticulum for apoB lipidation.

Hypolipidaemic mechanisms of action of CM108 (a flavone derivative) in hyperlipidaemic rats.

In the present study, the molecular mechanisms by which CM108, a flavone derivative, improves lipid profiles were investigated further. Hyperlipidaemia was induced by oral administration of high cholesterol and fat. After 4 weeks of treatment, the lipid levels in the serum, liver and faeces were measured and the liver genes involved in lipid metabolism were analysed to explore the molecular mechanisms of lowering lipids.

Anti-hyperlipidemic properties of CM108 (a flavone derivative) in vitro and in vivo.

Peroxisome proliferator-activated receptors (PPARs) and liver X receptor alpha are ligand-activated transcription factors that belong to nuclear receptors superfamily and are involved in the regulation of lipid metabolism. PPAR, especially PPAR-alpha, PPAR-gamma agonists and liver X receptor alpha agonists can regulate the expression or biosynthesis of some factors involved in the formation and function of HDL, such as apolipoprotein (apo) A-I and ATP binding cassette transporter A1 (ABCA1). It is well known that HDL plays an important role in the treatment of hyperlipidemia as the carrier of reverse cholesterol transport.