Nonalcoholic steatohepatitis (NASH) is increasing in prevalence, yet its consequences for liver function are unknown. We studied ureagenesis, an essential metabolic liver function of importance for whole body nitrogen homeostasis, in a rodent model of diet-induced NASH. Rats were fed a high-fat, high-cholesterol diet for 4 and 16 wk, resulting in early and advanced experimental NASH, respectively. We examined the urea cycle enzyme mRNAs in liver tissue, the hepatocyte urea cycle enzyme proteins, and the in vivo capacity of urea-nitrogen synthesis (CUNS). Early NASH decreased all of the urea cycle mRNAs to an average of 60% and the ornithine transcarbamylase protein to 10%, whereas the CUNS remained unchanged. Advanced NASH further decreased the carbamoyl phosphate synthetase protein to 63% and, in addition, decreased the CUNS by 20% [from 5.65 ± 0.23 to 4.58 ± 0.30 μmol × (min × 100 g)(-1); P = 0.01]. Early NASH compromised the genes and enzyme proteins involved in ureagenesis, whereas advanced NASH resulted in a functional reduction in the capacity for ureagenesis. The pattern of urea cycle perturbations suggests a prevailing mitochondrial impairment by NASH. The decrease in CUNS has consequences for the ability of the body to adjust to changes in the requirements for nitrogen homeostasis e.g., at stressful events. NASH, thus, in terms of metabolic consequences, is not an innocuous lesion, and the manifestations of the damage seem to be a continuum with increasing disease severity.

Background and AimData on quantitative metabolic liver functions in the life-threatening disease alcoholic hepatitis are scarce. Urea synthesis is an essential metabolic liver function that plays a key regulatory role in nitrogen homeostasis. The urea synthesis capacity decreases in patients with compromised liver function, whereas it increases in patients with inflammation. Alcoholic hepatitis involves both mechanisms, but how these opposite effects are balanced remains unclear. Our aim was to investigate how alcoholic hepatitis affects the capacity for urea synthesis. We related these findings to another measure of metabolic liver function, the galactose elimination capacity (GEC), as well as to clinical disease severity.MethodsWe included 20 patients with alcoholic hepatitis and 7 healthy controls. The urea synthesis capacity was quantified by the functional hepatic nitrogen clearance (FHNC), i.e., the slope of the linear relationship between the blood α-amino nitrogen concentration and urea nitrogen synthesis rate during alanine infusion. The GEC was determined using blood concentration decay curves after intravenous bolus injection of galactose. Clinical disease severity was assessed by the Glasgow Alcoholic Hepatitis Score and Model for End-Stage Liver Disease (MELD) score.ResultsThe FHNC was markedly decreased in the alcoholic hepatitis patients compared with the healthy controls (7.2±4.9 L/h vs. 37.4±6.8 L/h, P<0.01), and the largest decrease was observed in those with severe alcoholic hepatitis (4.9±3.6 L/h vs. 9.9±4.9 L/h, P<0.05). The GEC was less markedly reduced than the FHNC. A negative correlation was detected between the FHNC and MELD score (rho = -0.49, P<0.05).ConclusionsAlcoholic hepatitis markedly decreases the urea synthesis capacity. This decrease is associated with an increase in clinical disease severity. Thus, the metabolic failure in alcoholic hepatitis prevails such that the liver cannot adequately perform the metabolic up-regulation observed in other stressful states, including extrahepatic inflammation, which may contribute to the patients’ poor prognosis.

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Background and aimsHepatic cholesterol deposition drives inflammation and fibrosis in non-alcoholic steatohepatitis (NASH). The Niemann-Pick type C2 (NPC2) protein plays an important role in regulating intracellular cholesterol trafficking and homeostasis. We hypothesized that intravenous NPC2 supplementation reduces cholesterol accumulation, hepatic inflammation and fibrogenesis in a nutritional NASH rat model.MethodsRats were fed a high-fat, high-cholesterol (HFHC) diet for four weeks resulting in moderately severe NASH. Animals were treated with intravenous NPC2 or placebo twice weekly for either the last two weeks or the entire four weeks. End-points were liver/body- and spleen/body weight ratios, histopathological NASH scores, fibrosis, serum liver enzymes, cholesterol, lipoproteins, cytokines, and quantitative polymerase chain reaction derived hepatic gene expression related to cholesterol metabolism, inflammation, and fibrosis.ResultsHFHC rats developed hepatomegaly, non-fibrotic NASH histopathology, elevated liver enzymes, serum cholesterol, and pro-inflammatory cytokines. Their sterol regulatory element binding factor 2 (SREBF2) and low-density lipoprotein receptor (LDL-R) mRNAs were down-regulated compared with rats on standard chow. NPC2 did not improve liver weight, histopathology, levels of serum liver enzymes or pro-inflammatory tumor necrosis factor-α (TNFα), Interleukin (IL)-6, or IL-1β in HFHC rats. Two weeks of NPC2 treatment lowered hepatic TNFα and COL1A1 mRNA expression. However, this effect was ultimately reversed following additional two weeks of treatment. Four weeks NPC2 treatment of rats raised ATP-binding cassette A1 (ABCA1) and low-density lipoprotein receptor (LDLR) mRNAs in the liver, concurrent with a strong tendency towards higher serum high-density lipoprotein (HDL). Furthermore, the peroxisome proliferator activated receptor-ɣ (PPARG) gene expression was reduced.ConclusionsNPC2 proved inefficient at modifying robust hepatic NASH end-points in a HFHC NASH model. Nonetheless, our data suggest that hepatic ABCA1 expression and reverse cholesterol transport were upregulated by NPC2 treatment, thus presenting putative therapeutic effects in diseases associated with deregulated lipid metabolism.