Enhanced hepatic respiratory capacity and altered lipid metabolism support metabolic homeostasis during short-term hypoxic stress

Abstract Background Tissue hypoxia is a key feature of several endemic hepatic diseases, including alcoholic and non-alcoholic fatty liver disease, and organ failure. Hypoxia imposes a severe metabolic challenge on the liver, potentially disrupting its capacity to carry out essential functions including fuel storage and the integration of lipid metabolism at the whole-body level. Mitochondrial respiratory function is understood to be critical in mediating the hepatic hypoxic response, yet the time-dependent nature of this response and the role of the respiratory chain in this remain unclear. Results Here, we report that hepatic respiratory capacity is enhanced following short-term exposure to hypoxia (2 days, 10% O2) and is associated with increased abundance of the respiratory chain supercomplex III2+IV and increased cardiolipin levels. Suppression of this enhanced respiratory capacity, achieved via mild inhibition of mitochondrial complex III, disrupted metabolic homeostasis. Hypoxic exposure for 2 days led to accumulation of plasma and hepatic long chain acyl-carnitines. This was observed alongside depletion of hepatic triacylglycerol species with total chain lengths of 39-53 carbons, containing palmitic, palmitoleic, stearic, and oleic acids, which are associated with de novo lipogenesis. The changes to hepatic respiratory capacity and lipid metabolism following 2 days hypoxic exposure were transient, becoming resolved after 14 days in line with systemic acclimation to hypoxia and elevated circulating haemoglobin concentrations. Conclusions The liver maintains metabolic homeostasis in response to shorter term hypoxic exposure through transient enhancement of respiratory chain capacity and alterations to lipid metabolism. These findings may have implications in understanding and treating hepatic pathologies associated with hypoxia.

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Influence of short-term dexfenfluramine therapy on glucose and lipid metabolism in obese non-diabetic patients

Acta Endocrinologica ◽

10.1530/acta.0.1280251 ◽

1993 ◽

Vol 128 (3) ◽

pp. 251-258 ◽

Cited By ~ 19

Author(s):

Per H Andersen ◽

Bjørn Richelsen ◽

Jens Bak ◽

Ole Schmitz ◽

Niels S Sørensen ◽

...

Keyword(s):

Lipid Metabolism ◽

Serum Insulin ◽

Whole Body ◽

Glucose Disposal ◽

Total Serum ◽

Total Serum Cholesterol ◽

Diabetic Patients ◽

Obese Patients ◽

Short Term ◽

Glucose And Lipid Metabolism

In a short-term (eight days) double-blind crossover study involving 10 obese patients, the effects of dexfenfluramine on glucose and lipid metabolism were examined. The protocol comprised whole body in vivo measurements (hyperinsulinemic euglycemic clamp in combination with indirect calorimetry) and in vitro studies of isolated adipocytes (lipolysis and glucose transport). All study participants were weight stable during the study period (103.1±3.2, placebo vs 103.3±3.1 kg, dexfenfluramine, NS). The following parameters were significantly reduced after dexfenfluramine treatment: fasting levels of plasma glucose (6.2±0.2 vs 5.7±0.2 mmol/l, p<0.01), serum insulin (168.0±14.5 vs 138.9±7.9 pmol/l, p<0.05), serum C-peptide (0.68±0.03 vs 0.58±0.02 nmol/l, p<0.05) and total serum cholesterol (6.07±0.41 vs 5.48±0.38 mmol/l, p< 0.01). In the basal state glucose oxidation rate was significantly reduced by 36% (p<0.001), whereas non-oxidative glucose disposal was significantly increased by 41% (p<0.01), following dexfenfluramine treatment. Insulin-stimulated (2 mU·kg−1·min−1) glucose disposal rate tended to be increased (18%, p=0.10) after dexfenfluramine. In conclusion, dexfenfluramine possesses beneficial regulatory effects on glucose and lipid metabolism in non-diabetic obese patients, independently of weight loss.

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ChREBP-Mediated Regulation of Lipid Metabolism: Involvement of the Gut Microbiota, Liver, and Adipose Tissue

Frontiers in Endocrinology ◽

10.3389/fendo.2020.587189 ◽

2020 ◽

Vol 11 ◽

Author(s):

Katsumi Iizuka ◽

Ken Takao ◽

Daisuke Yabe

Keyword(s):

Adipose Tissue ◽

Fatty Acid ◽

Lipid Metabolism ◽

Gut Microbiota ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Acid Synthesis ◽

Whole Body ◽

Acetyl Coa ◽

Alcoholic Fatty Liver

Carbohydrate response element-binding protein (ChREBP) plays an important role in the development of type 2 diabetes, dyslipidemia, and non-alcoholic fatty liver disease, as well as tumorigenesis. ChREBP is highly expressed in lipogenic organs, such as liver, intestine, and adipose tissue, in which it regulates the production of acetyl CoA from glucose by inducing Pklr and Acyl expression. It has recently been demonstrated that ChREBP plays a role in the conversion of gut microbiota-derived acetate to acetyl CoA by activating its target gene, Acss2, in the liver. ChREBP regulates fatty acid synthesis, elongation, and desaturation by inducing Acc1 and Fasn, elongation of long-chain fatty acids family member 6 (encoded by Elovl6), and Scd1 expression, respectively. ChREBP also regulates the formation of very low-density lipoprotein by inducing the expression of Mtp. Furthermore, it plays a crucial role in peripheral lipid metabolism by inducing Fgf21 expression, as well as that of Angptl3 and Angptl8, which are known to reduce peripheral lipoprotein lipase activity. In addition, ChREBP is involved in the production of palmitic-acid-5-hydroxystearic-acid, which increases insulin sensitivity in adipose tissue. Curiously, ChREBP is indirectly involved in fatty acid β-oxidation and subsequent ketogenesis. Thus, ChREBP regulates whole-body lipid metabolism by controlling the transcription of lipogenic enzymes and liver-derived cytokines.

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Augmented effect of short-term pulsatile versus continuous insulin delivery on lipid metabolism but similar effect on whole-body glucose metabolism in obese subjects

Metabolism ◽

10.1016/0026-0495(94)90264-x ◽

1994 ◽

Vol 43 (7) ◽

pp. 842-846 ◽

Cited By ~ 17

Author(s):

O. Schmitz ◽

S.B. Pedersen ◽

A. Mengel ◽

N. Pørksen ◽

J. Bak ◽

...

Keyword(s):

Lipid Metabolism ◽

Glucose Metabolism ◽

Insulin Delivery ◽

Whole Body ◽

Short Term ◽

Obese Subjects

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Peroxisome Proliferator-Activated Receptor γ and Its Role in Adipocyte Homeostasis and Thiazolidinedione-Mediated Insulin Sensitization

Molecular and Cellular Biology ◽

10.1128/mcb.00677-17 ◽

2018 ◽

Vol 38 (10) ◽

Cited By ~ 9

Author(s):

Qiong A. Wang ◽

Fang Zhang ◽

Lei Jiang ◽

Risheng Ye ◽

Yu An ◽

...

Keyword(s):

Whole Body ◽

Peroxisome Proliferator ◽

Metabolic Homeostasis ◽

Short Term ◽

Peroxisome Proliferator Activated Receptor ◽

Fat Depots ◽

Metabolic Functions ◽

Sensitizing Effect

ABSTRACT Adipose tissue is a dynamic organ that makes critical contributions to whole-body metabolic homeostasis. Although recent studies have revealed that different fat depots have distinct molecular signatures, metabolic functions and adipogenic mechanisms, peroxisome proliferator-activated receptor γ (PPARγ) is still widely viewed as the master regulator of adipogenesis and critical for maintaining mature adipocyte function. Using an inducible, adipocyte-specific knockout system, we explored the role of PPARγ in mature adipocytes in vivo . Short-term PPARγ deficiency in adipocytes reduces whole-body insulin sensitivity, but adipocytes are viable both in vitro and in vivo . However, after exposure to a high-fat diet, even short-term PPARγ deficiency leads to rapid adipocyte death. When mature adipocytes are depleted of both PPARγ and CCAAT-enhancer-binding protein α (C/EBPα), they are rapidly depleted of lipids and undergo adipocyte death, both in vitro and in vivo . Surprisingly, although thiazolidinediones (TZDs; PPARγ agonists) are thought to act mainly on PPARγ, PPARγ in adipocytes is not required for the whole-body insulin-sensitizing effect of TZDs. This offers new mechanistic aspects of PPARγ/TZD action and its effect on whole-body metabolic homeostasis.

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Decreased Hepatic Lactotransferrin Induces Hepatic Steatosis in Chronic Non-Alcoholic Fatty Liver Disease Model

Cellular Physiology and Biochemistry ◽

10.1159/000491535 ◽

2018 ◽

Vol 47 (6) ◽

pp. 2233-2249 ◽

Cited By ~ 4

Author(s):

Sungmin Lee ◽

Beomseok Son ◽

Jaewan Jeon ◽

Gaeul Park ◽

Hyunwoo Kim ◽

...

Keyword(s):

Liver Disease ◽

Mouse Model ◽

Fatty Liver ◽

Hepatic Steatosis ◽

Fatty Liver Disease ◽

Dietary Lipids ◽

Whole Body ◽

Alcoholic Fatty Liver ◽

Hepatic Diseases ◽

Alcoholic Fatty Liver Disease

Background/Aims: Non-alcoholic fatty liver disease (NAFLD) is an emerging metabolic disease. Although it leads to severe hepatic diseases including steatohepatitis, cirrhosis, and hepatic cancer, little is known about therapy to prevent and cure hepatic steatosis, the first step of NAFLD. We conducted this investigation to unveil the mechanism of hepatic steatosis. Methods: We established a novel chronic NAFLD mouse model through whole body irradiation and verified the model through histological and biochemical analysis. To find molecular mechanism for hepatic steatosis, we analyzed hepatic transcriptomic profiles in this model and selected target molecule. To induce the expression of lactotransferrin (Ltf) and regulate the NAFLD, growth hormone (GH) and coumestrol was introduced to hepatocyte and mice. The universal effect of coumestrol was confirmed by administration of coumestrol to NAFLD mouse model induced by high-fructose, high-fat, and MCD diet. Results: It was observed that decreased hepatic Ltf expression led to excessive hepatic lipid accumulation in NAFLD mouse. Furthermore, we found that GH was decreased in irradiated mice and functioned as an upstream regulator of Ltf expression. It was observed that GH could stimulate Ltf expression and prevent uptake of dietary lipids in hepatocytes, leading to rescue of NAFLD. Finally, we suggested that coumestrol, a kind of isoflavonoid, could be used as an inducer of hepatic Ltf expression through cooperation with the GH signaling pathway both in vitro and in vivo. Conclusions: Hepatic Ltf prevents hepatic steatosis through inhibition of dietary lipid uptake in radiation-induced NAFLD mouse model. We also suggest coumestrol as a drug candidate for prevention of NAFLD.

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Short term mechanical stimulation using whole body vibration identifies differences in bone response between prepubertal boys with and without prior fracture

Bone Abstracts ◽

10.1530/boneabs.7.p25 ◽

2019 ◽

Author(s):

Rachel Harrison ◽

Kate Ward ◽

Alan Rigby ◽

Fatma Gossiel ◽

Nick Bishop

Keyword(s):

Mechanical Stimulation ◽

Whole Body Vibration ◽

Whole Body ◽

Short Term ◽

Body Vibration ◽

Bone Response ◽

Prior Fracture ◽

Prepubertal Boys

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Effects of short‐term heat acclimation on whole‐body heat exchange and local nitric oxide synthase‐ and cyclooxygenase‐dependent heat loss responses in exercising older men

Experimental Physiology ◽

10.1113/ep089025 ◽

2020 ◽

Author(s):

Naoto Fujii ◽

Gregory W. McGarr ◽

Sean R. Notley ◽

Pierre Boulay ◽

Ronald J. Sigal ◽

...

Keyword(s):

Nitric Oxide ◽

Heat Exchange ◽

Nitric Oxide Synthase ◽

Heat Loss ◽

Heat Acclimation ◽

Older Men ◽

Whole Body ◽

Short Term ◽

Oxide Synthase ◽

Body Heat

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How does hepatic lipid accumulation lead to lipotoxicity in non-alcoholic fatty liver disease?

Hepatology International ◽

10.1007/s12072-020-10121-2 ◽

2021 ◽

Vol 15 (1) ◽

pp. 21-35

Author(s):

Yana Geng ◽

Klaas Nico Faber ◽

Vincent E. de Meijer ◽

Hans Blokzijl ◽

Han Moshage

Keyword(s):

Lipid Metabolism ◽

Liver Disease ◽

Fatty Liver ◽

Lipid Accumulation ◽

Fatty Liver Disease ◽

Lipid Uptake ◽

Cellular Mechanisms ◽

Alcoholic Fatty Liver ◽

Lipid Species ◽

Alcoholic Fatty Liver Disease

Abstract Background Non-alcoholic fatty liver disease (NAFLD), characterized as excess lipid accumulation in the liver which is not due to alcohol use, has emerged as one of the major health problems around the world. The dysregulated lipid metabolism creates a lipotoxic environment which promotes the development of NAFLD, especially the progression from simple steatosis (NAFL) to non-alcoholic steatohepatitis (NASH). Purposeand Aim This review focuses on the mechanisms of lipid accumulation in the liver, with an emphasis on the metabolic fate of free fatty acids (FFAs) in NAFLD and presents an update on the relevant cellular processes/mechanisms that are involved in lipotoxicity. The changes in the levels of various lipid species that result from the imbalance between lipolysis/lipid uptake/lipogenesis and lipid oxidation/secretion can cause organellar dysfunction, e.g. ER stress, mitochondrial dysfunction, lysosomal dysfunction, JNK activation, secretion of extracellular vesicles (EVs) and aggravate (or be exacerbated by) hypoxia which ultimately lead to cell death. The aim of this review is to provide an overview of how abnormal lipid metabolism leads to lipotoxicity and the cellular mechanisms of lipotoxicity in the context of NAFLD.

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