The role of mitochondrial genomics in patients with non-alcoholic steatohepatitis (NASH).
Visceral obesity and metabolic syndrome are commonly associated with non-alcoholic fatty liver disease (NAFLD). The progression of steatosis to NASH depends on a number of metabolic and patient-related factors. The mechanisms of genetic predisposition towards the development of NASH and related fibrosis remain unclear. In this study, our aim was to utilize mitotyping and identify mitochondrial haplotypes that may be associated with NAFLD.



We examined mitochondrial haplotypes along with patatin-like phospholipase domain containing 3 (PNPLA3) rs738409 genotype to determine their association with NAFLD phenotypes. Whole blood samples were obtained from 341 patients (BMI > 35) undergoing weight reduction surgery after written consent. Liver biopsies were centrally reviewed by a single pathologist based on predetermined pathologic protocol (41.9 % Non-NASH NAFLD, 30.4 % NASH, 27.5 % controls). A 1,122 bp of the mitochondrial control loop was sequenced for each sample and classified into haplogroups.



The presence of haplogroup L exhibits protection against the development of NASH and pericellular fibrosis. The alleles of PNPLA3 locus showed differential distribution in cohorts with NAFLD, NASH and pericellular fibrosis. Heterozygosity at this locus is independently associated with higher risk of having NASH and pericellular fibrosis.



Mitochondrial genetics play an important role in NASH probably by modulation of oxidative stress and the efficiency of oxidative phosphorylation.
Betty and Guy Beatty Center for Integrated Research, Inova Fairfax Medical Campus, Falls Church, VA, USA.
Rohini
R
Mehta
Center for the Study of Chronic Metabolic and Rare Diseases, George Mason University, Fairfax, VA, 22033, USA.
Kianoush
K
Jeiran
Betty and Guy Beatty Center for Integrated Research, Inova Fairfax Medical Campus, Falls Church, VA, USA.
Aaron B
AB
Koenig
Betty and Guy Beatty Center for Integrated Research, Inova Fairfax Medical Campus, Falls Church, VA, USA.
Munkzhul
M
Otgonsuren
Betty and Guy Beatty Center for Integrated Research, Inova Fairfax Medical Campus, Falls Church, VA, USA.
Zachary
Z
Goodman
Center for the Study of Chronic Metabolic and Rare Diseases, George Mason University, Fairfax, VA, 22033, USA.
Ancha
A
Baranova
Betty and Guy Beatty Center for Integrated Research, Inova Fairfax Medical Campus, Falls Church, VA, USA. Zobair.younossi@inova.org.|Betty and Guy Beatty Center for Integrated Research, Claude Moore Center for Research and Education, 3300 Gallows Road, Falls Church, VA, 22033, USA. Zobair.younossi@inova.org.
Zobair
Z
Younossi
D000328:Adult; D001706:Biopsy; D005260:Female; D020022:Genetic Predisposition to Disease; D054629:Genome, Mitochondrial; D023281:Genomics / Q000379:methods; D006239:Haplotypes; D006801:Humans; D008049:Lipase / Q000235:genetics*; D008099:Liver / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics*; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA / Q000379:methods; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
D008049:Lipase; D008565:Membrane Proteins; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
Ethnicity; Hepatic fibrosis; Obesity; PNPLA3 rs738409