M. Ricchi

Differential effect of oleic and palmitic acid on lipid accumulation and apoptosis in cultured hepatocytes

Background and Aim:  Studies have shown monounsaturated oleic acid to be less toxic than palmitic acid and to prevent/attenuate palmitic acid hepatocites toxicity in steatosis models in vitro. However, to what degree these effects are mediated by steatosis extent is unknown.

Review article: hepatic steatosis and insulin resistance

Hepatic steatosis may be both an adaptive phenomenon and an example of lipotoxicity. Its prevalence ranks in the same order of magnitude of insulin resistance in the general population. Studies support the finding that hepatic steatosis is secondary to insulin resistance and not vice versa. A steatotic liver will further contribute to the development of insulin resistance through impaired clearance of insulin from the portal blood, creating a vicious cycle. Insulin resistance is the leading force in the pathogenesis and natural history of non‐alcoholic fatty liver disease. Dysfunction of energetic homeostasis and the interaction of adiponectin, leptin and tumour necrosis factor‐α are key events in the pathogenesis of steatosis and insulin resistance. Insulin resistance represents the frame within which hepatic and extrahepatic non‐alcoholic fatty liver disease‐related clinical manifestations are to be anticipated and interpreted.

Review article: the metabolic syndrome and non‐alcoholic fatty liver disease

Metabolic syndrome represents a common risk factor for premature cardiovascular disease and cancer whose core cluster includes diabetes, hypertension, dyslipidaemia and obesity. The liver is a target organ in metabolic syndrome patients in which it manifests itself with non‐alcoholic fatty liver disease spanning steatosis through hepatocellular carcinoma via steatohepatitis and cirrhosis. Given that metabolic syndrome and non‐alcoholic fatty liver disease affect the same insulin‐resistant patients, not unexpectedly, there are amazing similarities between metabolic syndrome and non‐alcoholic fatty liver disease in terms of prevalence, pathogenesis, clinical features and outcome. The available drug weaponry for metabolic syndrome includes aspirin, metformin, peroxisome proliferator‐activated receptor agonists, statins, ACE (angiotensin I‐converting enzyme) inhibitors and sartans, which are potentially or clinically useful also to the non‐alcoholic fatty liver disease patient. Studies are needed to highlight the grey areas in this topic. Issues to be addressed include: diagnostic criteria for metabolic syndrome; nomenclature of non‐alcoholic fatty liver disease; enlargement of the clinical spectrum and characterization of the prognosis of insulin resistance‐related diseases; evaluation of the most specific clinical predictors of metabolic syndrome/non‐alcoholic fatty liver disease and assessment of their variability over the time; characterization of the importance of new risk factors for metabolic syndrome with regard to the development and progression of non‐alcoholic fatty liver disease.

Age-related changes in bile acid synthesis and hepatic nuclear receptor expression.

Background  Recent data highlighted the role of nuclear receptors in the transcriptional regulation of the limiting enzyme of bile acid synthesis, cholesterol 7α‐hydroxylase, in cellular and animal models. This study was designed to analyze the effects of age on cholesterol 7α‐hydroxylase and related nuclear receptor expression in human livers.

Decreased hepatic expression of PPAR-gamma coactivator-1 in cholesterol cholelithiasis

Background  Cholesterol cholelithiasis (gallstone disease) is a common disease in the Western world. The aim of the present study was to analyze the hepatic expression of a number of nuclear receptors involved in bile acid metabolism in human cholesterol gallstone disease.

Effects of bile duct ligation and cholic acid treatment on fatty liver in two rat models of non-alcoholic fatty liver disease

BACKGROUND Non-alcoholic fatty liver disease, one of the most prevalent liver disorders in Western countries, is characterized by hepatic accumulation of triglycerides. Bile acids have long been known to affect triglyceride homeostasis through a not completely understood mechanism. AIM To analyse the effects of two different manipulations of bile acid circulation on non-alcoholic fatty liver disease. METHODS Two animal models of non-alcoholic fatty liver disease were developed by either feeding rats with a choline deficient or with a high fat diet. After 4 weeks, rats were randomized to undergo either bile duct ligation, sham operation or cholic acid administration. RESULTS During cholestasis there was an increased CYP7A1 expression, the rate limiting enzyme in bile acid synthesis, and a reduction of hepatic concentration of oxysterols, ligands of the liver X receptors. Target genes of the liver X receptors, involved in fatty acid and triglyceride synthesis, were down-regulated in association with decreased hepatic triglyceride content and improvement of fatty liver. Administration of cholic acid, ligand of farnesoid X receptor, also had a beneficial effect on fatty liver in rats on choline deficient diet. CONCLUSION These results indicate that pharmacological approaches increasing the expression of CYP7A1 or stimulating farnesoid X receptor pathway could represent a promising treatment for non-alcoholic fatty liver disease.

Correlation between plasma levels of 7alpha-hydroxy-4-cholesten-3-one and cholesterol 7alpha-hydroxylation rates in vivo in hyperlipidemic patients.

BACKGROUND/AIM Hepatic bile acid synthesis is the main mechanism whereby the organism can degrade cholesterol. Plasma levels of 7alpha-hydroxy-4-cholesten-3-one have been reported to reflect bile acid synthesis and the expression or activity of the limiting enzyme of the main biosynthetic pathway, cholesterol 7alpha-hydroxylase. Aim of this study was to correlate the levels of this metabolite with the rates of cholesterol 7alpha-hydroxylation in vivo, a direct measurement of bile acid synthesis, in hyperlipidemic patients. DESIGN Concentrations of 7alpha-hydroxy-4-cholesten-3-one were assayed by gas-liquid chromatography: mass spectrometry in plasma samples obtained in 18 patients with primary hyperlipoproteinemia who previously underwent determination of cholesterol 7alpha-hydroxylation rates in vivo by tritium release analysis. Both determinations were performed in basal conditions and after treatment with hypolipidemic drugs (the fibric acid derivatives gemfibrozil and bezafibrate, cholestyramine alone or associated with simvastatin). RESULTS Changes in plasma 7alpha-hydroxy-4-cholesten-3-one profile closely reflected in vivo cholesterol 7alpha-hydroxylation rates during treatment with fibrates, cholestyramine and cholestyramine plus simvastatin. When plotting determinations from all studies (n=40), a very strict correlation was disclosed between plasma 7alpha-hydroxy-4-cholesten-3-one and cholesterol 7alpha-hydroxylation rates (r=0.81, P<0.001). CONCLUSIONS Plasma 7alpha-hydroxy-4-cholesten-3-one closely mirrors measurements of cholesterol 7alpha-hydroxylation rates in vivo in hyperlipidemic subjects and therefore stands as a reliable marker of global bile acid synthesis. In view of the correlation observed, these data may help to interpret changes of plasma levels of this metabolite in terms of cholesterol balance quantification.

17β-estradiol prevents cytotoxicity from hydrophobic bile acids in HepG2 and WRL-68 cell cultures

Background:  Epidemiological and clinical studies suggest the possibility that estrogens might have a cytoprotective effect on the liver. The aim of the present study was to test the hypothesis that 17β‐estradiol (E2) prevents hepatocellular damage induced by deoxycholic acid (DCA), a hydrophobic bile acid.

The Neck-Liver Axis. Madelung Disease as Further Evidence for an Impact of Body Fat Distribution on Hepatic Histology

The article by Chand and Sanyal1 addresses an important issue and is very interesting and informative. Although the association between hyperbilirubinemia and sepsis is known to many clinicians, patterns and mechanisms of hyperbilirubinemia are not so well characterized. Furthermore, in settings in which hyperbilirubinemia may easily be explained by other factors (for instance by transient liver insufficiency after major liver resection) the responsibility of sepsis may be overlooked with a dangerous impact on outcome. Indeed, this is our setting. In an ongoing prospective study on liver resection patients, we have assessed a cumulative impact of sepsis, inadequate residual parenchymal volume, and duration of intraoperative normothermic ischemia in determining maximum postoperative plasma bilirubin (up to greater than 33.0 mg/dL, or 564 mol/L, in extreme cases). The effect of sepsis was to increase bilirubin or to cause an acute and transient peak overimposed on the pattern generated by the other factors. A striking observation was the tendency for a fairly constant relationship between conjugated and total bilirubin (regression slope 0.67, r2 0.98, P 0.001; n 263) which was independent of the prevailing factor (major resection, prolonged ischemia, sepsis). Alkaline phosphatase (AP) and gamma glutamyl transpeptidase (GGT) were normal or very slowly increasing, which was consistent with liver regeneration, and continued to slowly increase many weeks after surgery, when bilirubin was decreasing. The obvious exceptions were some larger increases in AP and GGT observed in patients with biliary sepsis or fistula. With regard to the article by Chand and Sanyal1, we wonder if the apparently similar and synergistic impact of inadequate liver volume, prolonged ischemia, and sepsis, with maintenance of a rather constant conjugated/total bilirubin ratio ( 2/3) may be consistent with a common and synergistic effect of these factors on hepatocellular bilirubin excretion (for instance, on multidrug resistance–associated protein activity), and whether this may have a clinical relevance, also for other treatments independent of that of sepsis. Very rare exceptions to this main pattern were observed outside the prospective period, and consisted of almost totally conjugated hyperbilirubinemia, larger increases in AP and GGT, and variable increases in aspartate aminotransferase and alanine aminotransferase. These were basically unrelated to sepsis, although sepsis could aggravate them, and had more complex or unfavorable outcomes. One of these patients had ischemic cholangitis after arterial thrombosis, other cases remained unexplained, and whether a small-forsize residual liver could have been a factor remains speculative. In conclusion, the authors1 should be congratulated for their effort, because many patterns of changes in plasma bilirubin are far from obvious in reality, and the relevance of their characterization extends far beyond the diagnosis of sepsis. The issue of sepsis is of utmost clinical importance in our setting, because the biochemical synergism of sepsis superimposed on liver insufficiency in increasing bilirubin is paralleled by a powerful synergism in worsening outcome. Finally there is a very minor inaccuracy in the article1 concerning the daily rate of production of bilirubin: although it is obvious that 4 mg per day should mean 4 mg/kg/day, this might require an “erratum”.