Table 1.

Comparison of human and rodent studies measuring intrahepatic DAG, hepatic PKCε translocation, intrahepatic ceramides, and hepatic insulin action. For rodent studies, hepatic insulin action was assessed as suppression of HGP during hyperinsulinemic-euglycemic clamp studies unless otherwise noted. Studies are listed in chronological order except when multiple studies describe the same model. n/a, not assessed. Rx, treatment. HFF, high-fat diet fed. ASO, antisense oligonucleotide. ZDF, Zucker diabetic fatty. STZ, streptozotocin.

Human studies
		Variable correlated to hepatic insulin resistance?
Reference	Readout of hepatic insulin resistance	IHTG	DAG	PKCε translocation	Ceramide	Notes
Kumashiro et al. (2011) [31]	HOMA-IR	Yes	Yes (both fractions)	Yes	No
Magkos et al. (2012) [35]	Clamp EGP suppression	n/a	Yes	n/a	No
Luukonen et al. (2016) [37]	HOMA-IR	Yes	Yes	n/a	Yes	Individual lipid species reported
Rodent studies
Reference	Model	Hepatic insulin action	IHTG	DAG	PKCε translocation	Ceramide	Notes
Models of perturbed hepatic triglyceride metabolism
Neschen et al. (2005) [46]	mtGPAT1 KO HFF mice	↑	↓	↓	↓	n/a	Individual DAG species reported
Nagle et al. (2007) [47]	mtGPAT1-overexpressing mice	↓	↑	↑	↑	n/a
Choi et al. (2007) [50]	DGAT2 ASO HFF rats	↑	↓	↓	↓	n/a
Zhang et al. (2007) [106]	LCAD KO mice	↓	↑	↑	↑	↔
Monetti et al. (2007) [51]	DGAT2-overexpressing mice	↔	↑	↑	n/a	↑
Jornayvaz et al. (2011) [52]	DGAT2-overexpressing mice	↓	↑	↑	↑	↑
Zhang et al. (2010)	VLCAD KO HFF mice	↑	↓	↓	↓	↔
Ryu et al. (2009) [49]	Lipin-1 knockdown in db/db mice	↑	↓	↓	n/a	n/a
Ryu et al. (2011) [48]	Lipin-2 overexpression in HFF mice	↓	↑	↑	n/a	n/a	ipGTT, ITT, HOMA-IR Individual DAG species reported
Ryu et al. (2011) [48]	Lipin-2 knockdown in HFF mice	↑	↓	↓	n/a	n/a	ipGTT, ITT, HOMA-IR Individual DAG species reported
Hoy et al. (2011) [107]	ATGL KO HFF mice	↑	↑	↓ (strong trend)	n/a	↓ (strong trend)	ipGTT, ITT
Turpin et al. (2011) [108]	ATGL hepatic overexpression in HFF mice	↑	↓	↓	↔	↓	Insulin signaling
Cantley et al. (2013) [57]	CGI-58 ASO HFF mice	↑	↑	↑ (lipid droplet) ↓ (membrane)	↓ (membrane)	↑ (all fractions)
Kumashiro et al. (2013) [109]	PNPLA3 ASO HFF rats	↑	↓	↓	↓	n/a
Hall et al. (2014) [59]	MGAT1 ASO HFF mice	↑	↔	↑ (all fractions)	↓ (membrane, total)	↔	Fasting insulin, ipGTT, insulin signaling
Soufi et al. (2014) [110]	MGAT1 ASO High trans-fat, fructose, cholesterol-fed mice	↑	↓	↔	n/a	n/a	ipGTT, insulin signaling
Trevino et al. (2015) [78]	Perilipin 5 hepatic overexpression in HFF mice	↔	↑	↑	n/a	↑	ipGTT, ITT
Models specifically testing the DAG-PKCε-INSR axis
Samuel et al. (2007) [43]	PKCε ASO 3d HFF rats	↑	↔	↔	↓	n/a
Raddatz et al. (2011) [44]	PKCε KO 7d HFF mice	↑	↑	↑	↓	n/a	ipGTT, HOMA-IR
Petersen et al. (2016) [45]	InsrT1150A 10d HFF mice	↑	↔	↔	↓	n/a
Models specifically testing the role of ceramides In hepatic Insulin resistance
Holland et al. (2007) [76]	Des1+/− mice	↑	n/a	n/a	n/a	↓	ITT, HOMA-IR
Holland et al. (2007) [76]	Myriocin Rx in ZDF rats	↑	n/a	↔	n/a	↓	oGTT, HOMA-IR
Yang et al. (2009) [86]	Myriocin Rx in HFF mice	↑	↓	n/a	n/a	n/a	ipGTT, ITT, insulin signaling
Holland et al. (2011) [84]	Adiponectin Rx in ob/ob mice	↑	n/a	↔	n/a	↓	Individual ceramide species reported
Holland et al. (2011) [81]	Lard oil infusion in mice	↓	n/a	↔	n/a	↑
Holland et al. (2011) [81]	Salicylate Rx in 17 wk HFF mice	↑	n/a	↔	n/a	↓	ITT, ipGTT
Raichur et al. (2014) [69]	CerS2+/− HFF mice	↓	↑	n/a	n/a	↑ (16:0) ↔ (total)	Fasting insulin, ipGTT, ITT
Turpin et al. (2014) [68]	CerS6 KO HFF mice	↑	n/a (but ↓ body weight and % fat)	n/a	n/a	↓ (16:0)	Fasting insulin, ipGTT, ITT, insulin signaling
Turpin et al. (2014) [68]	CerS6 liver-specific KO HFF mice	↑	n/a (but ↓ weight gain on HFD)	n/a	n/a	↓ (16:0)	ipGTT
Xia et al. (2015) [61]	Liver-specific overexpression of acid ceramidase in HFF mice	↑	↓	↑	n/a	↓ (16:0, 18:0, 20:0)
Xia et al. (2015) [61]	Adipose-specific overexpression of acid ceramidase in HFF mice	↑	↓	n/a	n/a	↓ (16:0, 18:0)
Holland et al. (2017) [96]	Adipose-specific overexpression of AdipoR1/2	↑	↓	n/a	n/a	↓ (16:0, 18:0)	Individual ceramide species reported
Holland et al. (2017) [96]	Liver-specific overexpression of AdipoR1/2	↑	↓	n/a	n/a	↓ (16:0, 18:0)	Individual ceramide species reported
Miscellaneous studies examining relationships between hepatic lipids and hepatic insulin action
Turinsky et al. (1990) [29]	ZDF rats	n/a	n/a	↑	n/a	↑	Insulin resistance assumed
Savage et al. (2006) [40]	ACC1/2 ASO HFF rats	↑	↓	↓	↓	n/a
Samuel et al. (2006) [111]	FOXO1 ASO HFF mice	↑	↓	↓	n/a	n/a	Individual DAG species reported
Choi et al. (2007) [112]	ACC2 KO HFF mice	↑	↓	↓	↓	n/a
Matsuzaka et al. (2007) [113]	ELOVL6 KO HFF mice	↑	↔	↓	↔	↔	ipGTT, fasting insulin insulin signaling
Jaworski et al. (2009) [114]	Adipocyte phospholipase A2 KO mice	↓	↑	↑	n/a	n/a
Erion et al. (2009) [42]	CREB ASO HFF+STZ rats	↑	↓	↓	↓	n/a
Ussher et al. (2010) [74]	12 wk HFF mice	↓	↑	n/a	n/a	↔	ipGTT, ITT
Jornayvaz et al. (2010) [115]	Ketogenic diet fed mice	↓	↑	↑	↑	↑
Birkenfeld et al. (2011) [41]	mINDY KO HFF mice	↑	↓	↓	↓	↔
Lee et al. (2011) [77]	ApoC3 overexpressing HFF mice	↓	↑	↑	↑	↔
Jornayvaz et al. (2012) [116]	Thyroid hormone receptor-α KO HFF mice	↑	↓	↓	↓	n/a
Jurczak et al. (2012) [117]	XBP1 conditional KO fructose-fed mice	↑	↓	↓	↓	↑
Brown et al. (2012) [118]	FAAH KO HFF mice	↓	↑	↑	↑	↔
Sun et al. (2012) [119]	Liver-specific HDAC3 KO mice	↑	↑	↑	↔	↔
Camporez et al. (2013) [33]	FGF-21 Rx HFF mice	↑	↓	↓	↓	↔
Camporez et al. (2013) [38]	Estradiol Rx ovariectomize d HFF female mice	↑	↓	↓	↓	↔
Galbo et al. (2013) [75]	3d HFF rats (saturated or unsaturated)	↓	↑	↑	↑	↔
Perry et al. (2013) [24]	DNP-ME Rx HFF rats	↑	↓	↓	↓	↔
Montgomer y et al. (2013) [72]	8 wk HFF mice (BL/6, 129X1, DBA/2, FVB/N)	↓	↑	↑	n/a	↔	ipGTT, HOMA-IR
Turner et al. (2013) [71]	1 wk HFF BL/6 mice	↓	↑	↑	n/a	↔	Individual lipid species reported
Turner et al. (2013) [71]	3 wk HFF BL/6 mice	↓	↑	↑	n/a	↔ (16:0, 18:0) ↑ (20:0, 22:0) ↓ (24:0, 24:1)	Individual lipid species reported
Turner et al. (2013) [71]	16 wk HFF BL/6 mice	↓	↑	↑	n/a	↔ (16:0, 22:0) ↑ (18:0, 20:0) ↓ (24:0, 24:1)	Individual lipid species reported
Zhu et al. (2014) [120]	Liver-specific estrogen receptor KO male HFF mice	↓	↑	↑	n/a	n/a
Camporez et al. (2015) [34]	ApoA5 ASO HFF mice	↑	↓	↓	↓	↑
Perry et al. (2015) [23]	CRMP Rx HFF rats	↑	↓	↓	↓	↔	Individual DAG species reported
Chan et al. (2015) [121]	Fenofibrate Rx HFF mice	↑	↔	↔ (total) ↑ (lipid droplet) ↓ (membrane)	n/a	↔ (lipid droplet, membrane)	ipGTT, insulin signaling
Jordy et al. (2015) [122]	Exercise in HFF mice	↑	↓	↓	n/a	↔	Fasting insulin, oGTT Individual lipid species reported
Aroor et al. (2015) [123]	DPP-4 inhibitor Rx in Western diet-fed mice	↑	↓	↓	n/a	↔	Individual lipid species reported
Shang et al. (2016) [124]	Duodenal-jejunal bypass surgery in HFF mice	↑	↓	↓	n/a	↓ (20:0, 22:0) ↔(16:0, 18:0)	Individual lipid species reported
Wilson et al. (2016) [125]	Liver-specific CD36 KO in HFF mice	↑	↓	↓	n/a	↔	ipGTT, ITT
Popov et al. (2016) [126]	β-catenin ASO in HFF mice	↑	↓	↓	↓	↑
Abulizi et al. (2017) [39]	CRMP Rx A/ZIP fatless mice	↑	↓	↓ (all fractions)	↓	↔