Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is currently the world’s most common liver disease, estimated to affect up to one-fourth of the population. Hallmarked by hepatic steatosis, NAFLD is associated with a multitude of detrimental effects and increased mortality. This narrative review investigates the molecular mechanisms of hepatic steatosis in NAFLD, focusing on the four major pathways contributing to lipid homeostasis in the liver. Hepatic steatosis is a consequence of lipid acquisition exceeding lipid disposal, i.e., the uptake of fatty acids and de novo lipogenesis surpassing fatty acid oxidation and export. In NAFLD, hepatic uptake and de novo lipogenesis are increased, while a compensatory enhancement of fatty acid oxidation is insufficient in normalizing lipid levels and may even promote cellular damage and disease progression by inducing oxidative stress, especially with compromised mitochondrial function and increased oxidation in peroxisomes and cytochromes. While lipid export initially increases, it plateaus and may even decrease with disease progression, sustaining the accumulation of lipids. Fueled by lipo-apoptosis, hepatic steatosis leads to systemic metabolic disarray that adversely affects multiple organs, placing abnormal lipid metabolism associated with NAFLD in close relation to many of the current life-style-related diseases.     

Depression by ethionine of phosphorylating oxidation in hepatic mitochondria

Induction of hepatic steatosis and suppression of hepatic ATP levels, protein synthesis and gluconeogenesis subsequent to administration of ethionine may be consequences of interference by this compound with mitochondrial phosphorylation of ADP. The mitochondrial dysfunction is not a direct action of ethionine on the organelle.     

Effects of gonadal hormones on the lipid contents of the frogRana esculenta

Summary The effects of exogenous gonadal hormones on the lipid contents of the liver and ovary and also on water content in the frog,Rana esculenta, were studied. Estrogen treatment significantly enhanced, whereas testosterone treatment reduced, the lipid and cholesterol contents. Water content of the frogs increased significantly after treatment by either hormone.Acknowledgment. I wish to thank Dr Hussain Al-Adhub, College of Science for providing all necessary laboratory facillities. Present address: Physiology Laboratory, Department of Zoology, Patna University, Patna-80005, Bihar (India).     

Depression by ethionine of phosphorylating oxidation in hepatic mitochondria

Summary Induction of hepatic steatosis and suppression of hepatic ATP levels, protein synthesis and gluconeogenesis subsequent to administration of ethionine may be consequences of interference by this compound with mitochondrial phosphorylation of ADP. The mitochondrial dysfunction is not a direct action of ethionine on the organelle.     

The assembly of lipids into lipoproteins during secretion

The process of assembly and secretion of lipoproteins is discussed with particular reference to the role of lipids. The majority of circulating lipoproteins is produced by the liver (80%) with the remainder being supplied by the intestine. The liver secretes both very low density lipoproteins and high density lipoproteins, but the assembly and secretion of these two types of particles may follow different routes. The major lipid components of lipoproteins are triacylglycerols, cholesterol, cholesterol esters and phospholipids. The biosynthesis of these lipids occurs on membranes of the endoplasmic reticulum, with many of the enzymes also being present in the Golgi; the roles of these two subcellular organelles in the assembly of lipoproteins are discussed. There appears to be a compartmentalization of lipids in cells, such that defined pools, often those newly-synthesized, are preferred, or even required, for lipoprotein assembly. The process of hepatic very low density lipoprotein secretion appears to be regulated by the supply of lipids. Indeed, the synthesis of new lipid may be a major driving force in lipoprotein assembly and secretion.     

The assembly of lipids into lipoproteins during secretion

Summary The process of assembly and secretion of lipoproteins is discussed with particular reference to the role of lipids. The majority of circulating lipoproteins is produced by the liver (80%) with the remainder being supplied by the intestine. The liver secretes both very low density lipoproteins and high density lipoproteins, but the assembly and secretion of these two types of particles may follow different routes. The major lipid components of lipoproteins are triacylglycerols, cholesterol, cholesterol esters and phospholipids. The biosynthesis of these lipids occurs on membranes of the endoplasmic reticulum, with many of the enzymes also being present in the Golgi; the roles of these two subcellular organelles in the assembly of lipoproteins are discussed. There appears to be a compartmentalization of lipids in cells, such that defined pools, often those newly-synthesized, are preferred, or even required, for lipoprotein assembly. The process of hepatic very low density lipoprotein secretion appears to be regulated by the supply of lipids. Indeed, the synthesis of new lipid may be a major driving force in lipoprotein assembly and secretion.     

Cytochalasin D is able to mimic the effects of phalloidin on the rat liver

Summary Cytochalasin D induces a strong potassium release in the isolated perfused rat liver and leads to vacuolization of the liver parenchymal cells. These effects are similar to the action of phalloidin on the rat liver. Since phalloidin and cytochalasin act in a different way on microfilaments, it is suggested that any disturbance of the function of microfilaments can induce these effects.Acknowledgment. I thank Professor Th. Wieland for his interest in this investigation. The technical assistance of Iris Gilbert is very much appreciated.     

ABCB4 missense mutations D243A,K435T,G535D,I490T,R545C,and S978P significantly impair the lipid floppase and likely predispose to secondary pathologies in the human population

Bile salts are natural detergents required to solubilise dietary fat and lipid soluble vitamins. They are synthesised in hepatocytes and secreted into the luminal space of the biliary tree by the bile salt export pump (BSEP), an ATP-binding cassette (ABC) transporter in the canalicular membrane. BSEP deficiency causes cytotoxic accumulation of bile salts in the hepatocyte that results in mild-to-severe forms of cholestasis. The resulting inflammation can also progress to hepatocellular cancer via a novel mechanism involving upregulation of proliferative signalling pathways. A second ABC transporter of the canalicular membrane is also critical for bile formation. ABCB4 flops phosphatidylcholine into the outer leaflet of the membrane to be extracted by bile salts in the canalicular space. These mixed micelles reduce the detergent action of the bile salts and protect the biliary tree from their cytotoxic activity. ABCB4 deficiency also causes cholestasis, and might be expected to cause cholangitis and predispose to liver cancer. Non-synonymous SNPs in ABCB4 have now been described in patients with liver cancer or with inflammatory liver diseases that are known to predispose to cancer, but data showing that the SNPs are sufficiently deleterious to be an etiological factor are lacking. Here, we report the first characterisation at the protein level of six ABCB4 variants (D243A, K435T, G535D, I490T, R545C, and S978P) previously found in patients with inflammatory liver diseases or liver cancer. All significantly impair the transporter with a range of phenotypes exhibited, including low abundance, intracellular retention, and reduced floppase activity, suggesting that ABCB4 deficiency is the root cause of the pathology in these cases.     

On geometric objects,the non-existence of a gravitational stress-energy tensor,and the uniqueness of the Einstein field equation

The question of the existence of gravitational stress-energy in general relativity has exercised investigators in the field since the inception of the theory. Folklore has it that no adequate definition of a localized gravitational stress-energetic quantity can be given. Most arguments to that effect invoke one version or another of the Principle of Equivalence. I argue that not only are such arguments of necessity vague and hand-waving but, worse, are beside the point and do not address the heart of the issue. Based on a novel analysis of what it may mean for one tensor to depend in the proper way on another, which, en passant, provides a precise characterization of the idea of a “geometric object”, I prove that, under certain natural conditions, there can be no tensor whose interpretation could be that it represents gravitational stress-energy in general relativity. It follows that gravitational energy, such as it is in general relativity, is necessarily non-local. Along the way, I prove a result of some interest in own right about the structure of the associated jet bundles of the bundle of Lorentz metrics over spacetime. I conclude by showing that my results also imply that, under a few natural conditions, the Einstein field equation is the unique equation relating gravitational phenomena to spatiotemporal structure, and discuss how this relates to the non-localizability of gravitational stress-energy. The main theorem proven underlying all the arguments is considerably stronger than the standard result in the literature used for the same purposes (Lovelock's theorem of 1972): it holds in all dimensions (not only in four); it does not require an assumption about the differential order of the desired concomitant of the metric; and it has a more natural physical interpretation.     

Unsaturated lipid droplets in liver sinusoids lining cells in a case of Reye-Morgan-Baral syndrome.

The author reports a case of Reye-Morgan-Baral syndrome presenting osmiophilic-dense lipidic bodies in lining cells of hepatic sinusoids. The different lipidic saturation level between the content of these bodies and the one of lipid droplets of hepatocytes could represent a different response, between hepatocytes and lining cells of liver sinusoids, to excessive circulating lipids.     

A simple method of obtaining multiple blood samples from the portal vein and the hepatic vein in the rat in vivo

A very simple and rapid technique for inserting a catheter in the portal vein and the hepatic vein in the anesthesized rat in vivo is described. The pointed, saline-containing PE tubing is frozen in liquid nitrogen, whereupon it is used as a 'needle' to insert the catheter into the blood vessel. Multiple blood samples can be obtained from the portal and the hepatic vein at the same time, so that in situ extraction of drugs by the liver can be measured in vivo, since hepatic blood flow is uninterrupted.     

Thyroid hormone controls carnitine status through modifications of γ-butyrobetaine hydroxylase activity and gene expression

The carnitine system plays a key role in β-oxidation of long-chain fatty acids by permitting their transport into the mitochondrial matrix. The effects of hypothyroidism and hyperthyroidism were studied on γ-butyrobetaine hydroxylase (BBH), the enzyme responsible for carnitine biosynthesis in the rat. In rat liver, BBH activity was decreased in the hypothyroid state and increased in hyperthyroid animals. The modifications in BBH activity correlated with changes in the enzyme Vmax values. These changes were shown to be related to hepatic BBH mRNA abundance. Thyroid hormones are known to interact with lipid metabolism, in particular by increasing long-chain fatty acid oxidation through activation of carnitine-dependent fatty acid import into mitochondria. Our study showed that thyroid hormones also increased carnitine bioavailability. Received 23 October 2001; received after revision 11 January 2002; accepted 15 January 2002     

Glucose-evoked recovery of hepatic thyroxine 5'-deiodinase independent of de novo protein synthesis in fasted rat

The glucose-evoked recovery of Type I thyroxine 5'-deiodinase activity in the hepatic microsomes of fasted rat was not inhibited by either cycloheximide, puromycin or actinomycin D during 3 h after glucose feeding; however, [3H]-leucine uptake by the liver or the hepatic microsomal fraction was significantly inhibited by cycloheximide and puromycin but not by actinomycin D. These results indicate that the glucose-evoked recovery of deiodinase activity may be independent of de novo protein synthesis.     

Leibniz’s syncategorematic infinitesimals

In contrast with some recent theories of infinitesimals as non-Archimedean entities, Leibniz’s mature interpretation was fully in accord with the Archimedean Axiom: infinitesimals are fictions, whose treatment as entities incomparably smaller than finite quantities is justifiable wholly in terms of variable finite quantities that can be taken as small as desired, i.e. syncategorematically. In this paper I explain this syncategorematic interpretation, and how Leibniz used it to justify the calculus. I then compare it with the approach of Smooth Infinitesimal Analysis, as propounded by John Bell. I find some salient differences, especially with regard to higher-order infinitesimals. I illustrate these differences by a consideration of how each approach might be applied to propositions of Newton’s Principia concerning the derivation of force laws for bodies orbiting in a circle and an ellipse. “If the Leibnizian calculus needs a rehabilitation because of too severe treatment by historians in the past half century, as Robinson suggests (1966, 250), I feel that the legitimate grounds for such a rehabilitation are to be found in the Leibnizian theory itself.”—(Bos 1974–1975, 82–83).