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Table 4 Summary of genes differentiating FUNG, FISH, and COMB. Summary of genes differentiating FUNG, FISH, and COMB. Included are a subset of the most important genes selected from Table 3. The predicted global metabolic effect (up or down regulation) mediated by the differentiating group relative to other groups, is shown in the first column. The 2nd column shows the differentiating group. The differentially regulated genes, and their direction of change, are shown in column 3, with signaling cascades in column 4. For example, relative to other groups, FUNG up regulated apoptosis via down regulation of the apoptosis inhibitor diap1, via JUN-RHOA signaling. TF, transcription factor.

From: How dietary arachidonic- and docosahexaenoic- acid rich oils differentially affect the murine hepatic transcriptome

Metabolic effect of gene change

Differentiating group

Gene changes

Signaling pathway

Amino acid: tyrosine & ornithine metabolism

FUNG

dct↓, sf3a2↑, oat↑

CTNB1

Protein synthesis

FUNG

eef1a1↓

 

Apoptosis↑

FUNG

Diaph1↓ (apoptosis inhibitor)

JUN-RHOA

Apoptosis↓

FISH

dvl2↓

CTNB1/MAPK9 and -10 activation

Apoptosis↑

FISH

Camk2b↓

INS1/hRAS/SAG/I κBα, P27KIP1

Apoptosis↑

FISH

Nfkbia↓

NFκB signaling

Apoptosis↑/↓ G1/S progression

COMB

atf4↓, atf5↓

bZIP TF

Biliary bicarbonate secretion↓

FISH<FUNG

slc4a2↓

 

Bile acid uptake by hepatocytes↓

FISH

slc10a1↓

 

Biliary cholesterol secretion↓

COMB

aqp8↓

SREBP1a

Carbohydrate metabolism

COMB

foxa3↓, hnf3g↓, g6pc↓

foxa3: INS1-FOXA2

Carbohydrate metabolism

COMB; FUNG<FISH

bat2↓

CTNB1

Cell proliferation↑

FUNG<FISH

dusp9↓

JUN-CDKN2A. DUSP phosphatases inhibit MK

Cell proliferation↑

FUNG

ppp1ca↓

INS1-hRAS

Cell proliferation↑

FUNG>FISH

Ptpra↑

activates Src tyr kinases

Cell proliferation↑

FUNG<FISH

ptpn1↓, ppp2cb↓

 

Cell proliferation↓

FUNG<FISH; COMB

ighmbp2↓

TGFβ 1-HGF

Cell proliferation↓

FUNG

cyp24↓ (↑1,25(OH)2D3)

VDRE-PXR signaling

Cell proliferation↓

FUNG

ccnb1↓ (codes cyclin B1)

CDK1 activation

Cell proliferation↓

FUNG

tcfeb↓, barx1↓, notch2↓

 

Cell proliferation↓

FUNG<FISH; COMB

tcfe3↓

bHLH-zip TF

Cell proliferation↑

FISH

bop1↓

MYC

Cell proliferation↑/Lipid transport↑

FISH

cd36↑

PPARα signaling

Cell proliferation↑/Lipid transport↑

FISH

abce1↑

FABP-SNCA

Cell proliferation↓

FISH

tcea2↓

MYC-POL2RA

Cell proliferation↓

FISH

usf2↓

bHLH TF

Cell proliferation↓

FISH

jund↓, yy1↓

bHLHzip TF: IL6-TNF signaling

Cell proliferation↓

FISH

hoxa13↓

TGFβ 1-BMP2

Cell proliferation↓

FISH

fgfr3↓

INS1-STAT3

Cell proliferation↓

FISH

cdk4↓

D-cyclin-INK4a

Cell proliferation↓

FISH

tef↓

 

Cell proliferation

FISH

rab5c↓ (phosphatase; GTPase)

 

Cell proliferation

FISH

eef2↓ (activity depends on P state)

 

Cell proliferation↓

COMB

plk1↓ (Zn finger)

CTNB1

Cell proliferation↓

COMB

Rgs16↑

JUN-TNF-G protein coupled receptor

Cell proliferation

COMB

atf5↓

bzip TF

Cell proliferation

COMB

ntrk1↓ (receptor tyr kinase)

INS1/hRAS

Cell proliferation

COMB

eprs↓ (activity depends on P state)

TGFβ 1-IKBKb

Clotting↓

FISH

serpinc1↑

 

Collagen synthesis↓

FUNG

plod3↓

 

Cytoskeletal effects

COMB

acta2↓, arhgef7↓, sn↓, tubb2↓, tubb3↓

CTNB1

FA β-Oxidation↑

ALL

acadm↑, crat↑, cpt1a↑, cpt2↑, ech1↑

PPARα signaling

AcetylCoA biosynthesis↓

COMB

acas2↓

 

AcylCoa binding↓

COMB

dbi↓

MYC

FA synthesis/desaturation↓

COMB

acly↓ thrsp↓, fasn (FUNG<FISH)↓, scd↓

INS1, SREBP, PPARα, TNF

FA elongation↑

FISH

elovl2/3↑

 

Cyt P450 metabolism↑

FISH

4a10↑, 4a14↑ (affect ion channel activity, vascular tone)

PPARα signaling

FA transported into liver↓

FUNG

slc27a1↓

JUN-TNF-PPARα

Lipid transport↓

FISH

fabp5↓

TGFβ 1-PPARα

Lipoprotein metabolism

FUNG

apoc1↓

INS1

Lipoprotein metabolism: reverse cholesterol transport↑

FISH

apoe↑ (↓ cholesterol and TAG)

 

Lipoprotein metabolism: transport↓

COMB

apoa4↓

PPARα signaling

Galactose binding↓

FUNG

lgal3↓

CTNB1

Heme synthesis

FUNG

alas1↑, alas2↓

INS1-STAT3

Hemoglobin synthesis↑

FISH>FUNG

hba-a1↑, hbb-b1↑

 

Immune system

COMB

tcf2↓, tcf7↑

MYC-PCAF-CREBP; CTNB1

Oxidative stress

COMB

hpx↓

TGFβ 1-LEP

Oxidative stress: aldehyde dehydrogenases↑

FISH

aldh1a7↑, aldh2↑ aldh1a1↑

SREBP1a

Oxidative stress: peroxidases↑

FISH

gpx1↑, prdx2↑, prdx4↑, mpo↑

 

Oxidative stress: heat shock proteins

FISH vs FUNG

hspb1 (HSP25/27)↓, hspcb↑

ERK, PKCδ, TGFβ, p38, MK2/TNFα, IL1β, NFκB