The metabolomic window into hepatobiliary disease

Abstract

The emergent discipline of metabolomics has attracted considerable research effort in hepatology. Here we review the metabolomic data for non-alcoholic fatty liver disease (NAFLD), non-alcoholic 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) develops. 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.

Keywords: Cirrhosis; Core metabolomic phenotype; Hepatocellular carcinoma; Metabolic remodelling; Metabolomics; NAFLD; NASH; Warburg effect.

Fig. 1. Major liver diseases and potential influencing factors

This schematic shows the development of NAFLD from a healthy liver various influencing factors (green boxes). Steatosis is shown in yellow. NAFLD mostly becomes isolated fatty liver, but some cases progress to NASH, showing both steatosis and inflammatory necrosis (shown in red and black). NASH may progress to cirrhosis and then to HCC or to HCC directly. HCC, cirrhosis and decompensated cirrhosis may all be treated by liver transplantation. Chemical carcinogens, such as aflatoxin B₁, together with alcohol and HBV and HCV infection, are all potential influencing factors (green boxes). Abbreviations used: NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; HCC, hepatocellular carcinoma; HBV, hepatitis B virus; HCV, hepatitis C virus.

Fig. 2. Mechanisms leading to lowered LPCs and elevated bile acids in serum in NASH

Reproduced with permission from Tanaka et al. Disruption of phospholipid and bile acid homeostasis in mice with nonalcoholic steatohepatitis. Hepatology 2012;56:118–129. Abbreviations used: LPC, lysophosphatidylcholine.

Fig. 3. Venn diagram showing the up- and down-regulated metabolites in NAFLD/NASH, cirrhosis and HCC

Elevated bile acids and lowered lysophosphatidylcholines are common across the pathological evolution in humans and comprise a core metabolomic phenotype. For abbreviations, see Fig. 1.

Fig. 4. Diverse hepatic insults leading to a core metabolomic phenotype en route from the healthy liver to HCC and CCA

Elevated serum bile acids and urinary bile salts together with decreased serum lysophosphatidylcholines represent the core metabolomic phenotype (CMP). A metabolic remodelling begins in the transition from the healthy liver (Phase 0) to NAFLD/NASH, ALD or viral hepatitis (Phase 1). During Stage 1 there occurs a Warburg shift from mitochondrial respiration to cytosolic glycolysis, together with an increase in fatty acid β-oxidation. This metabolic remodelling persists through cirrhosis (Phase 2) and into carcinoma (Phase 3). Note that the sum of the carcinoma energy production D+E+F is greater than the summed energy production A+B+C in the healthy liver. Abbreviations used: CCA, cholangiocarcinoma; CMP, core metabolomic phenotype; ALD, alcoholic liver disease. For other abbreviations, see Fig. 1.