Team players in the pathogenesis of metabolic dysfunctions-associated steatotic liver disease: The basis of development of pharmacotherapy

Table 1 Peroxisome proliferator-activated receptor-α functions[101]

Organ/tissue	Positive regulation	Negative regulation
Liver	↑ ApoAI; ↑ ApoAII; ↑ ApoAV	↓ Apoptosis
	↑ Cholesterol catabolism	↓ HL
	↑ FA oxidation and activation	↓ Inflammation
	↑ Fatty acid oxidation genes	↓ Oxidative stress
	↑ FATP; ↑ FAT/CD3	↓ Proteolysis of SREBF1
	↑ Gluconeogenesis and glycolysis	↓ SREBF2
	↑ Insig1
	↑ Ketogenesis
	↑ Lipogenesis
	↑ LPL and triglyserides clearance
Skeletal muscle	↑ FA oxidation gene	↓ Glucose intolerance
	↑ FA oxidation
	↑ Insulin sensitivity
Cardiac muscle	↑ AT2 receptor	↓ AT1 receptor
	↑ FA uptake	↓ Cardiac hypertrophy and inflammation
	↑ FA oxidation	↓ Genes for glucose uptake and oxidation
		↓ ED-1 (CD68) expression
		↓ NF-κB activity
		↓ VCAM-1, ICAM-1
		↓ Platelet and endothelial cell adhesion
Plasma	↑ HDL	↓ ApoC3
	↑ RCT	↓ Dyslipidemia
		↓ Inflammation
		↓ IFN-γ
		↓ TNFα
		↓ sdLDL
		↓ VLDL-triglyserides

Apo: Apoprotein; AT1: Endothelin-1 receptor; AT2: Endothelin-2 receptor; IFN-γ: Interferon gamma; FA: Fatty acid; FATP: Fatty acid transport protein; ICAM-1: Insig-1: Insulin induced gene-1; LPL: Lipoprotein lipase; RCT: Reverse cholesterol transport; sdLDL: Small-dense LDL; VCAM-1: Vascular cell adhesion molecules-1; TNFα: Tumor necrosis factor-alpha.

Table 2 List of common genetic variants with their effect and association[218]

Gene	Variant	Impact on protein	Effect of the variant	Allelic frequency Europeans	Hispanics	Asians	Africans	Effect size	Direction of association (Ancestral allele)	Fat	NASH	Fibrosis	HCC	Mortality	Response to the therpaies
PNPLA3	rs738409 C>G	I148M	Complex: Loss- plus gain-of-function	0.23	0.57	0.38	0.14	+++	Up	+	+	+	+	+	+
TM6SF2	rs58542926 C>T	E167K	Loss-of-function	0.08	0.03	0.07	0.04	+++	Up	+	+	+	+		+
GCKR	rs1260326 T>C	P446L	Loss-of-function	0.6	0.67	0.5	0.86	+	Up	+	+	+	+
MBOAT7	rs641738 C>T	Linked to 3'-UTR	Reduced expression	0.42	0.33	0.24	0.34	+	Up	+	+	+	+
HSD17B13	rs72613567 T>TA rs62305723 G>A	Alternate splicing P260S	Loss-of-function	0.27 0.07	0.09 0.02	0.34	0.06 0.01	++	Down		+	+
IL28B (IFNL3/4)	rs368234815 TT>dG	Alternate protein translation site	Alternative protein	0.27	0.09	0.34	0.06	+	Down		+	+
MERTK	rs4374383 G>A	Noncoding variant	Reduced expression	0.37	0.37	0.73	0.47	+	Down			+

HCC: Hepatocellular carcinoma; NASH: Nonalcoholic steatohepatitis.