The mevalonate pathway produces isoprenoids that are vital for diverse cellular functions, ranging from cholesterol synthesis to growth control. Several mechanisms for feedback regulation of low-density-lipoprotein receptors and of two enzymes involved in mevalonate biosynthesis ensure the production of sufficient mevalonate for several end-products. Manipulation of this regulatory system could be useful in treating certain forms of cancer as well as heart disease.

Regulation of the mevalonate pathway.

Background. Infection with Helicobacter pylori has been linked with chronic atrophic gastritis, an inflammatory precursor of gastric adenocarcinoma. In a nested case–control study, we explored whether H. pylori infection increases the risk of gastric carcinoma. Methods. From a cohort of 128,992 persons followed since the mid-1960s at a health maintenance organization, 186 patients with gastric carcinoma were selected as case patients and were matched according to age, sex, and race with 186 control subjects without gastric carcinoma. Stored serum samples collected during the 1960s were tested for IgG antibodies to H. pylori by enzyme-linked immunosorbent assay. Data on cigarette use, blood group, ulcer disease, and gastric surgery were obtained from questionnaires administered at enrollment. Tissue sections and pathology reports were reviewed to confirm the histologic results. Results. The mean time between serum collection and the diagnosis of gastric carcinoma was 14.2 years. Of the 109 patient...

https://www.nejm.org/doi/pdf/10.1056/NEJM199110173251603

Helicobacter pylori infection and the risk of gastric carcinoma.

Methods for assessment, e.g., anthropometric indicators and imaging techniques, of several phenotypes of human obesity, with special reference to abdominal fat content, have been evaluated. The correlation of fat distribution with age, gender, total body fat, energy balance, adipose tissue lipoprotein lipase and lipolytic activity, adipose tissue receptors, and genetic characteristics are discussed. Several secreted or expressed factors in the adipocyte are evaluated in the context of fat tissue localization. The body fat distribution and the metabolic profile in nonobese and obese individuals is discussed relative to lipolysis, antilypolysis and lipogenesis, insulin sensitivity, and glucose, lipid, and protein metabolism. Finally, the endocrine regulation of abdominal visceral fat in comparison with the adipose tissue localized in other areas is presented.

/pdf/subcutaneous-and-visceral-adipose-tissue-their-relation-to-5crse4rslq.pdf

Subcutaneous and visceral adipose tissue : Their relation to the metabolic syndrome

Plasma-high-density-lipoprotein concentration and development of ischæmic heart-disease

The hepatic stellate cell has surprised and engaged physiologists, pathologists, and hepatologists for over 130 years, yet clear evidence of its role in hepatic injury and fibrosis only emerged following the refinement of methods for its isolation and characterization. The paradigm in liver injury of activation of quiescent vitamin A-rich stellate cells into proliferative, contractile, and fibrogenic myofibroblasts has launched an era of astonishing progress in understanding the mechanistic basis of hepatic fibrosis progression and regression. But this simple paradigm has now yielded to a remarkably broad appreciation of the cell's functions not only in liver injury, but also in hepatic development, regeneration, xenobiotic responses, intermediary metabolism, and immunoregulation. Among the most exciting prospects is that stellate cells are essential for hepatic progenitor cell amplification and differentiation. Equally intriguing is the remarkable plasticity of stellate cells, not only in their variable intermediate filament phenotype, but also in their functions. Stellate cells can be viewed as the nexus in a complex sinusoidal milieu that requires tightly regulated autocrine and paracrine cross-talk, rapid responses to evolving extracellular matrix content, and exquisite responsiveness to the metabolic needs imposed by liver growth and repair. Moreover, roles vital to systemic homeostasis include their storage and mobilization of retinoids, their emerging capacity for antigen presentation and induction of tolerance, as well as their emerging relationship to bone marrow-derived cells. As interest in this cell type intensifies, more surprises and mysteries are sure to unfold that will ultimately benefit our understanding of liver physiology and the diagnosis and treatment of liver disease.

/pdf/hepatic-stellate-cells-protean-multifunctional-and-enigmatic-1ctrvjmfhn.pdf

Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver

Extraction and recombination studies of the interaction of retinol with human plasma retinol-binding protein

Biochemical characteristics of isolated rat liver stellate cells

Chylomicrons containing labeled cholesterol, mainly (70%) present as cholesteryl ester, were injected intravenously into intact rats, and samples of liver were obtained 27–210 min later Most (58–75%) of the injected label was recovered in the liver after 27–75 min Hepatic uptake occurred without hydrolysis of the labeled cholesteryl ester In separate experiments, in vitro perfusion of livers of similarly treated rats for 30–35 min washed out only 3–9% of the labeled sterol Samples of liver and small intestine were prepared for electron microscopy with Aquon as the dehydrating agent Good retention (70% or more) of labeled cholesterol and satisfactory preservation of ultrastructure were obtained After 30 min, the radioautographic reaction was localized mainly over the region of the cell boundary of the parenchymal liver cells, with fewer grains being present over intracellular organelles At later time intervals, when considerable hydrolysis of the labeled cholesteryl ester had occurred, the radioautographic reaction was more evenly distributed Phagocytosed labeled lipid was seen in Kupffer cells after the larger lipid load; phagocytosis by parenchymal cells was not seen In other experiments, cholesteryl ester hydrolase activity was found in all subcellular fractions, the microsome and plasma membrane fractions showing the highest activity per mg protein The mechanism of cholesteryl ester transport into the liver cell may involve: (1) hydrolysis at the cell surface; or (2) slow entry of intact molecules followed by intracellular hydrolysis of the ester bond

https://rupress.org/jcb/article-pdf/43/3/410/1069299/410.pdf

THE METABOLISM OF CHYLOMICRON CHOLESTERYL ESTER IN RAT LIVER: A Combined Radioautographic-Electron Microscopic and Biochemical Study

This study reports the isolation and partial characterization of vitamin D and 25-hydroxyvitamin D binding protein (DBP), the specific transport protein for vitamin D and its 25-hydroxy metabolite in human plasma. DBP was labeled by the addition of a tracer amount of 3H-labeled 25-OH-D3 to the original plasma used for protein fractionation. Previous experiments have shown that such 25-OH-D3 added in vitro binds to the same protein normally responsible for the transport of endogenous 25-OH-D and of vitamin D. The isolation of human DBP was achieved by an extensive sequence of procedures which resulted in a final yield of only approximately 4 mg of purified DBP from a starting volume of 34 liters of plasma. Purified DBP was homogeneous in the analytical ultracentrifuge and showed a single band of protein on analytical polyacrylamide gel electrophoresis. DBP had a sedimentation constant of 3.49s and a mol wt of approximately 52,000. The molecular weight was assessed by sedimentation equilibrium analysis and also by sodium dodecyl sulfate-disc-gel electrophoresis and by gel filtration on a standardized column of Sephadex G-150. The amino acid composition of DBP was determined and was generally consistent with the estimated extinction coefficient (E1cm1% at 280 nm) of about 9.1. The isoelectric point of DBP was estimated as 4.8 from isoelectric focusing experiments. Direct study of the binding capacity of the purified DBP for added 25-OH-D3 showed that the isolated DBP had a high affinity for 25-OH-D3, with an apparent maximum binding capacity of one molecule of 25-OH-D3 per molecule of protein.

/pdf/the-transport-of-vitamin-d-and-its-25-hydroxy-metabolite-in-1gvp3qpqdo.pdf

The transport of vitamin D and its 25-hydroxy metabolite in human plasma. Isolation and partial characterization of vitamin D and 25-hydroxyvitamin D binding protein.

Studies were conducted to examine in detail the effects of vitamin A deficiency on fetal growth and development in the rat. The gradations of deficiency were examined in two studies. The first included total vitamin A depletion followed by retinoic acid supplements, and the second included three different levels of restricted intake of retinyl acetate (42, 16, or 8 mug of retinol equivalents/day/kg of body weight) in vitamin A-depleted rats. In the first study, extensive fetal resorption and death were observed in retinoic acid-fed females after day 14 of gestation. These findings confirmed the morphological studies of Thompson and associates (Proc. Roy. Soc. London, Ser. B 159, 510-535, 1964) who found the earliest Detectable histological lesions to be in the placentas at days 15-16 of pregnancy. Analyses were carried out of the total weight, the DNA, RNA, and protein contents of fetuses and placentas of different gestational ages in retinyl ester-fed and retinoic acid-fed females. Biochemical changes indicative of a reduced rate of cell division were observed in both fetus and placenta by day 14 in the retinoic acid-fed rats. The few live fetuses in this group maintained a growth rate of only 60-70% of that of the fetuses of retinyl ester-fed dams after day 14. By contrast, the growth rate of the placentas (of live fetuses) after day 14 of gestation was not as consistently affected by retinol deficiency. Restriction of retinyl acetate intake (in the second study) significantly reduced both the total litter size and the number of live pups per litter. Most of the females in the retinyl acetate-restricted groups delivered pups that had normal body weight and appeared normal on visual inspection. Significant differences from normal controls were seen only in the neonates from dams given 8 mug of retinol equivalents (per kg of body weight per day), which had smaller livers and kidneys than the control neonates. In contrast, the weights of the brains of the neonates in all three retinyl acetate-restricted groups showed no differences from control values. Vitamin A assays on maternal and neonatal sera and livers indicated that the transport of vitamin A across the placenta was well regulated, and suggested that this transport is maintained with high priority in the presence of maternal deficiency. The effects of vitamin A deficiency on fetal growth and development might reflect primary effects on the placenta, with secondary effects on the fetus, or primary direct effects on the fetus itself. The mechanisms of the observed effects remain to be explained.

DeWitt S. Goodman

Papers

Extraction and recombination studies of the interaction of retinol with human plasma retinol-binding protein

Biochemical characteristics of isolated rat liver stellate cells

THE METABOLISM OF CHYLOMICRON CHOLESTERYL ESTER IN RAT LIVER: A Combined Radioautographic-Electron Microscopic and Biochemical Study

The transport of vitamin D and its 25-hydroxy metabolite in human plasma. Isolation and partial characterization of vitamin D and 25-hydroxyvitamin D binding protein.

Vitamin A Deficiency and Fetal Growth and Development in the Rat