The metabolomic window into hepatobiliary disease

Abstract

Summary The emergent discipline of metabolomics has attracted considerable research effort in hepatology. Here we review the metabolomic data for nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), cirrhosis, hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), alcoholic liver disease (ALD), hepatitis B and C, cholecystitis, cholestasis, liver transplantation and acute hepatotoxicity in animal models. A metabolomic window has permitted a view into the changing biochemistry occurring in the transitional phases between a healthy liver and hepatocellular carcinoma or cholangiocarcinoma. Whether provoked by obesity and diabetes, alcohol use or oncogenic viruses, the liver develops a core metabolomic phenotype (CMP) that involves dysregulation of bile acid and phospholipid homeostasis. The CMP commences at the transition between the healthy liver (Phase 0) and NAFLD/NASH, ALD or viral hepatitis (Phase 1). This CMP is maintained in the presence or absence of cirrhosis (Phase 2) and whether or not either HCC or CCA (Phase 3) develop. Inflammatory signalling in the liver triggers the appearance of the CMP. Many other metabolomic markers distinguish between Phases 0, 1, 2 and 3. A metabolic remodelling in HCC has been described but metabolomic data from all four Phases demonstrate that the Warburg shift from mitochondrial respiration to cytosolic glycolysis foreshadows HCC and may occur as early as Phase 1. The metabolic remodelling also involves an upregulation of fatty acid β-oxidation, also beginning in Phase 1. The storage of triglycerides in fatty liver provides high energy-yielding substrates for Phases 2 and 3 of liver pathology. The metabolomic window into hepatobiliary disease sheds new light on the systems pathology of the liver.

OC-022 Addressing the interplay between apoptosis and glucose metabolism in liver cirrhosis and HCC

“…It was demonstrated that this metabolic shift occurs during the transition from healthy and early stage of liver injury (NAFLD/NASH, ALD to late stage of disease (i.e. cirrhosis), and further escalates during HCC development [1,2]. This metabolic signature enables dividing cells to satisfy anabolic and energetic needs for biomass production and to suppress apoptotic signalling, which is consistent with increased compensatory hepatic cell proliferation typical of cirrhotic and HCC livers.…”

Lipid Metabolism in Liver Cancer

“…As a manifestation of steatosis, the lipogenesis (triacylglycerols, diacylglycerol, and phospholipids) [51][52][53] and bile acid biosynthesis (cholesterol esters, choline, and bile acids) [54,55] pathways were found to be up-regulated. The hepatic lipids were found to be rearranged and repartitioned from adipose to liver, rather than de novo lipogenesis and deposition in the liver, possibly through increased turnover of phosphatidylcholine and phosphatidylethanolamine [9]. This conclusion was supported by a mouse starvation experiment that TG(44:2) and TG(48:3), the most abundant triacylglycerols in adipose, were significantly deposited in the liver after 24-h starvation [52].…”

“…Beyoglu and Idle in the University of Bern, Switzerland [9], recently well summarized the metabolomic findings conducted in chronic liver diseases and HCC, and proposed a threestage biochemical progression from healthy liver to carcinoma through intermediate phases of chronic liver diseases including NAFLD/NASH and cirrhosis, according to the alterations of major metabolites and the involved metabolic pathways. A common alteration of "core metabolic phenotype [9]" was found between liver diseases and healthy liver. Deregulation of bile acid and phospholipid occurred in the early phase of NAFLD/NASH, and maintained in cirrhosis and HCC.…”

“…As same as the other omics technologies, the metabolomic investigations have provided new insights into liver disease mechanisms and identified novel biomarkers involved in liver diseases and oncogenesis. Recent findings, comparing different phases of liver diseases from healthy liver to NAFLD/NASH, cirrhosis, and eventually HCC, revealed that both Warburg shift (from mitochondrial oxidative phosphorylation to enforced cytosolic glycolysis) and the up-regulation of lipid catabolism occurred as early as in NAFLD/NASH, and throughout the whole oncogenic processes [9].…”

Pre-clinical and clinical investigations of metabolic zonation in liver diseases: The potential of microphysiology systems

“…19 Although NASH patients have elevated serum bile acids and decreased lysophosphatidylcholine, the relationship between NASH and zone-specific functions remains largely unknown. 20 Mantena et al 21 found dysregulated oxygen gradient and mitochondrial effects in a high-fat diet NAFLD disease model in the mouse from which he postulates NASH and NAFLD alters the sinusoidal oxygen gradient so that zone 1 hepatocytes consume more oxygen but puts zone 2 and zone 3 hepatocytes into severe hypoxia ....................................................................................................................... in KO mice. Hepatic HIF1a is an important oxygensensitive transcriptional regulator of glycolysis.…”