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Genome-scale study reveals reduced metabolic adaptability in patients with non-alcoholic fatty liver disease

ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is a major risk factor leading to chronic liver disease and type 2 diabetes. Here we chart liver metabolic activity and functionality in NAFLD by integrating global transcriptomic data, from human liver biopsies, and metabolic flux data, measured across the human splanchnic vascular bed, within a genome-scale model of human metabolism. We show that an increased amount of liver fat induces mitochondrial metabolism, lipolysis, glyceroneogenesis and a switch from lactate to glycerol as substrate for gluconeogenesis, indicating an intricate balance of exacerbated opposite metabolic processes in glycemic regulation. These changes were associated with reduced metabolic adaptability on a network level in the sense that liver fat accumulation puts increasing demands on the liver to adaptively regulate metabolic responses to maintain basic liver functions. We propose that failure to meet excessive metabolic challenges coupled with reduced metabolic adaptability may lead to a vicious pathogenic cycle leading to the co-morbidities of NAFLD.

INSTRUMENT(S): Leco Pegasus 4D GC×GC-TOFMS

PROVIDER: MTBLS298 | MetaboLights | 2016-12-15

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS298_catheterization_study_metabolite_profiling_mass_spectrometry.txt	Txt
	a_xstudy_metabolite_profiling_mass_spectrometry.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS298_catheterization_study_metabolite_profiling_mass_spectrometry_v2_maf.tsv	Tabular
	s_MTBLS298.txt	Txt

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Genome-scale study reveals reduced metabolic adaptability in patients with non-alcoholic fatty liver disease.

Hyötyläinen Tuulia T Jerby Livnat L Petäjä Elina M EM Mattila Ismo I Jäntti Sirkku S Auvinen Petri P Gastaldelli Amalia A Yki-Järvinen Hannele H Ruppin Eytan E Orešič Matej M

Nature communications 20160203

Non-alcoholic fatty liver disease (NAFLD) is a major risk factor leading to chronic liver disease and type 2 diabetes. Here we chart liver metabolic activity and functionality in NAFLD by integrating global transcriptomic data, from human liver biopsies, and metabolic flux data, measured across the human splanchnic vascular bed, within a genome-scale model of human metabolism. We show that an increased amount of liver fat induces mitochondrial metabolism, lipolysis, glyceroneogenesis and a switc ...[more]

PMID: 26839171

Similar Datasets

Project description:Non-alcoholic fatty liver disease (NAFLD), defined as fatty infiltration in >5% of hepatocytes (steatosis) in the absence of excessive alcohol consumption, is emerging as a leading cause of liver disease worldwide (1). Subjects with NAFLD have an increased risk of progressing into non-alcoholic steatohepatitis (NASH) as well as developing type 2 diabetes, cardiovascular disease, and liver cancer (2-4). Thus, understanding the pathobiology of NAFLD is of high medical relevance for the efficient prevention and treatment of a range of complex metabolic diseases. In NAFLD, excess lipids accumulate within intrahepatocellular lipid droplets (LDs), which are composed of a neutral lipid core of mainly triacylglycerol (TAG) and cholesterol esters surrounded by a phospholipid monolayer that harbors specific proteins. Once thought to be only inert energy storage depots, hepatic LDs are increasingly recognized as organelles that orchestrate liver lipid partitioning but also play a critical role in protein quality control and storage, cell signaling, and viral replication (5). Notably, LDs are shown to dynamically interact with a variety of cellular organelles including the endoplasmic reticulum (ER), mitochondria, peroxisomes, and endosomes (6). Liver LD surface-associated proteins regulate the functional properties of LDs, and dietary fat content as well as liver metabolic status have been shown to dynamically influence the composition of hepatic LD proteins (7, 8). Consequently, exploring how LD-associated proteins affect hepatic metabolism is important for understanding the molecular pathophysiology of NAFLD. In the search for novel targets that regulate ectopic lipid accumulation in the context of nutritional stress and obesity, we identified serine/threonine protein kinase (STK)25, a member of the Ste20 kinase superfamily (9), as a hepatic LD-associated protein, which critically controls the development and progression of NAFLD (10-15). We found that STK25 knockdown attenuates lipid deposition in human hepatocytes and mouse liver by repressing lipid synthesis and enhancing β-oxidation and very-low-density lipoprotein (VLDL)-TAG secretion, with the reciprocal phenotype seen when STK25 protein is overexpressed (10-15). Notably, administration of hepatocyte-targeting GalNAc-conjugated Stk25 antisense oligonucleotide (ASO) in obese mice effectively ameliorates diet-induced hepatic steatosis as well as NASH features (i.e., liver inflammation, hepatocellular ballooning, and fibrosis), providing in vivo nonclinical proof-of-principle for the metabolic benefit of pharmacological STK25 inhibitors (15). Furthermore, we observed that STK25 levels in human liver biopsies correlate with the severity of NASH, and several common non-linked single nucleotide polymorphisms (SNPs) in the human STK25 gene are associated with altered liver fat content (12-14). Although these studies suggest a key role for STK25 in the control of liver LD dynamics, the mechanism-of-action of STK25 in regulation of hepatic lipid partitioning has remained elusive. To provide novel insights into biological function of STK25 in the liver under steatotic conditions, we here characterized the hepatic LD-associated phosphoproteome in Stk25 knockout mice and their wild-type littermates following high-fat diet feeding using non-biased approach by isobaric tagging for relative quantification. Of the 4,515 proteins and 982 phosphoproteins identified with a 1% false discovery rate, we report a total of 131 proteins and 69 phosphoproteins that were differentially represented in STK25-deficient livers. Most notably, a number of proteins involved in peroxisomal function, antioxidant defense, and ubiquitination-mediated proteolysis were coordinately regulated in the livers from high-fat-fed Stk25-/- mice compared with wild-type controls.